UNIVERSITY OF IBADAN LIBRARY IN SEARCH OF AN ANTIDOTE FOR A POISONED WORLD An iruurguml lecture delivered at the University of Ib- 2 JOHN IBIIAGBEMLEN ANETOR Professor of Chemical Pathology and Toxicology Faculty of Basic Medical Sciences University of lbadan Ibadan, Nigeria UNIVERSITY OF IBADAN UNIVERSITY OF I ADAN LIBRARY The Vice-C hancellor, Depuv Vice-Chancellor (Admini- stration), Deputy Vice-Chancellor (Academic), Registrar, Librarian, Provost of the College of Medicine, Dean of the Faculty of Basic Medicid Sciences, Deun of the Postgraduate School, Deans of other Faculties and of Stdrats, Directors of Institutes, Distinguished h&es und Gentlemen. QUOTES Does the dose alone determine the poison? What is there that is not poison? All things are poison and nothing (is) without poison. Solely the dose determines that a thing is not poison. Paracelsus (1493- 1541) W e are poisoning the air over our cities, we are poisoning the rivers and the seas; we are poisoning the soil itself. Some of this may be inevitable. But if we do not get together in a real and mighty effort to stop these attacks upon Mother Earth, wherever possible, we may find ourselves one day- one day soon, may be- in a world that will be only a desert full of plastic, concrete and electronic robots. In that world there wiIl be no more, nature'; in that world man and a few domestic animals will be the only living creatures. And yet, man cannot live without some measure of contact with nature. It is essential to his happiness. -Prince Bernard of the Netherlands. In publishing this book we wish to contribute our share in reviving the personality of an honest man who was a great physician and a staunch fighter for what he considered the truth. It is so easy to be orthodox and to reap honors by repeating what people expect and wish to hear. Progress, UNIVERSITY OF IBADAN LIBRARY however, is achieved through the clash of ideas, and heretics like Paracelsus are a ferment without which there would be no life" -Henry E. Sigerist [In the preface to his book Parocelsus, Four Treatise 19581. Preamble It gives me great pleasure to stand before this distinguished and &gust audience to give this lecture. It is God who truly takes all the glory as we will wme to see and appreciate. It is He who had preordained everything as I have come to realize in my life and that I am just stepping into the s b c h e d pathway. I thank the ViceChancellor for this opportunity. By my calculation I would have been on my way out before it gets to my turn. I also thank my Dean, Professor Olusegun George Ademowo for nominating me to give the lecture. I do not know how it all started but I juit h e w t hat I had this love and reverence for scholars and sch~lmhipi n whatever field and yearned to be one. I am glad that God made me one. God used my mother and her relations to ensure that my dream is realized. As king James the First observed, 'were I not a king I would be a university man' (James 1606). I am not a king but I thank God that He made me a university man. The Department of Chemical Pathology, University of Ibadsn Chemical pathology is one of the foundation departments of the then Faculty of Medicine which has grown into the College of Medicine. The department is organized into five main units as follow: Endocrine and Metabolism Unit Nutrition and Lipid Metabolism Unit Immunology Unit (soon to be a full DepartmIat of Immunology) Toxicology (and Micronutrient Metabolism) Unit (previously Trace Element Metabolism Unit) Repmductive Endocrinology Unit UNIVERSITY OF IBADAN LIBRARY This is the 5" inaugural lecture coming from the Department of Chemical Pathology. The first was given by Professor David Olatunbosun, MD, from the Toxicology and Micronutrient Metabolism Unit, followed by Professor Babatunde Osotimehin, MD from the Reproductive Endocrinology Unit; the third was from Professor Emmanuel 0. Agbedana, Ph.D from the Nutrition and Lipid Metabolism Unit. The fourth was given by Professor Francis A.A. Adeniyi, Ph.D from the Toxicology and Micronutrient Metabolism Unit and the fifth is today being delivered by me from the same Toxicology and Micronutrient Metabolism Unit. Mr. Vice-Chancellor, Sir, the broad lay out of the lecture shall be as follows: Brief overview of my journey into medical science Today's world as a chemical habitat Unearthing the combat between chemicals of life and the chemicals of prosperity Research in the Laboratory for Toxicology and Micronutrient Metabolism (describing my contribu- tion; highlighting: - overthrow of the chemicals of life by the chemicals of prosperity, disease and death. - toxic responseslconsequences and lamentation - traditional roles of a chemical pathologist - a new remit for the contemporary chemical pathologist - mechanistic search for an antidote for a poisoned and hungry (susceptible) world - the antioxidant hypothesis and the antioxidant controversy Concluding remarks (today's toxicity of the academic environment) Recommendations Acknowledgements UNIVERSITY OF IBADAN LIBRARY To know what you prefer, instead of humbly saying Amen to what the worold tells you ought to prefer, is to have ke-pt your soul alive ' IobeHL Stevenom The Annunciation: Journey into Medid Science and Chemical Patholu$g Just before my school certificate examination, an uncle of mine, indeed, my most senior uncle, Late Mr. Henry Emrnosele Eimunjeze who was one of the foundation staff of the Chemistry Department in the then Midwest Institute of Technology (M.LT.) which metamorphosed to University of Benin, Benin City, mentioned to me of a byear course called Medical Laboratory Technology at the time. He said it was a very good and promising discipline that he wanted a member of the family good in science to take advantage of it. He promised to assist me with admission if I accepted to study the course. During the A-Level Science Course at the Faculty of &en% University of badan, I did not forget wh& my s e w uncle told me. C o h & ~ J y ,I ccame across an advai&emmt ifor a d m i s s h imta the programme at the Wverslry College (UCHA and Ibadan leadimg to the Associate ~mbership'o f the Institute of Medical Laboratory Technology (AIMLT). I told my younger uncle, Uncle Vincent what uncle Henj told me but he did not show any interest. All he said was that he was told that one had to h o w the 'big professors in UCH to get admission'. He promised to contact his friend who said he had no power to help. All the same I went ahead and applied and continued with my AnRvel studies in Biology, ~he&strya nd Physics. I wrote so many letters to my senior uncle, at Uniben, he never replied. One day he visited Ibadan and told me that he had changed his mind, that I should go and read medicine or any of the biological sciences as he did not want 'a bright boy like me to be frustrated'. He told me of how Late Professor A-mbrose Alli started with the course and had to change to medicine as well as many of his former class mates at Edo College, Benin. I went ahead and sat for the examination. UNIVERSITY OF IBADAN LIBRARY About 300 of us must have sat for the examination at Paul Hendricks's Lecture Hall at the then Faculty of Medicine, UCH in 1976. I was not hopeful as I was told that they will take only ten out of the three hundred of us. Surprisingly, I was invited for the interview. T had to look for information about the course and the practitioners. Those days we used to spend almost all day on Saturdays at the British Council Library, Dugbe if we did not have classes at the university in our An programme. It .was while I was in the library, I think I must have been on my way to the toilet when my eyes caught a book, 'Ask The Lab: Introduction to the Profession of Medical Laboratory Technology'. I cannot remember the author but one thing shocked me, why is it that I was coming across the book now that I am preparing for the interview. I thanked Gad, read the book which introduced me to the profession, the various branches and their functions- Chemical Pathology, Haematolog y and Blood Transfusion, Histopathology, Microbiology, Parasitology and Virology, not too sure about the latter. There and then I made up my mind that were I to be given admission, I would specialize in Chemical Pathology; laden with ' chemistry (my best and beloved subject) and biochemistry. I went for the interview, I knew I did very well, I still recall that one of the people who interviewed me was Emeritus Professor Grace Olaniyan- Taylor, FAS, who later turned out to be my supervisor for my M.Sc. and Co-Supervisor of my Ph.D and has remained a mother ever since. Before I got close to her, I used to admire her elegance and comportment from a distance as an undergraduate student. I am glad I had the opportunity to be mentored by her. Medical Laboratory Science Medical laboratory science refers to a defined field of study related to the clinical investigation of disease. It may be funnall y defined as the application of basic sciences, especially the biological sciences to the study of medicine, in particular, the causes, consequences, diagnosis, and treatment of human diseases. It is called by different names in different UNIVERSITY OF IBADAN LIBRARY countries, from medical technology to clinical laboratory science in America and Canada, Biomedical Science in the United Kingdom, Clinical Biology in France, Medical Science in Australia and New Zealand. Thus, the practitioners of medical laboratory science are scient ificdl y qualified professionals who conduct investigations on specimens removed from humans and animals largely for the diagnosis, treatment or prevention of disease (Glencross et al. 201 1). They are relatively -unknown because they are typically active in more laboratory-based work and tend to have relatively limited contact with patients compared with other healthcare professionals. Scientists as we know need serene noiseless environment to do their work. As will be clearly evident medical laboratory science is very closely related to pathology, in which they have very strong foundation. Pathology may basically be defined as the science of disease. It is a discipline bridging clinical practice and basic science. The scientific focus of pathology is on the cause (aetiology ) of disease, the mechanism of its development (pathogenesis) and pathways by which biochemical and morphological changes (alterations) occur. These fundamental events occur at the molecular and cellular levels and it is there that our studies commence. Medical laboratory science and pathology therefore are at least first cousins. The core of the training in medical laboratory science revolves around biology and all applied forms, chemistry, pathobiology of human disease and analytical methods. This gives rise to the broad specialties as follow: The broad specialties of medical laboratory science are: . Chemical pathology or Clinical Biochemistry- involving the study of chemicals, biochemicals and . biochemical mechanisms, and their imbalances within the body how this gives rise to disease. Cwcal biochemistry is about patients, how they are investigated for their symptoms, diagnosed and how they are treated. Further elaboration follows below. UNIVERSITY OF IBADAN LIBRARY Hamatology here often combined with blood transfusion science, largely the study of the morphology and physiology of blood related diseases. The blood transfusion component involves studying blood and blood products to ensure they are fit for a needing recipient or patient. Medical Microbiology is concerned with the detection, isolation and identification of micro- organisms, including bacteria, fungi that cause disease and treatment of diagnosed disease. Histopathology, this involves use of the microscopic changes in the study of tissues to identify disease that may be present. This is almost all, the only discipline the public knows about pathology and medical laboratory science. They say they deal with the dead, which is not completely true; we actually deal more with the living than the dead. Immunology - involves study of the functioning of the immune system of the body, or its responses to disease with an overall goal of defending or protecting the the host. It is known as the unifying science among all the laboratory science or medicine discipline; studied in all the branches. Virology - involved in the detection, isolation and identification of vimses and associated diseases. I will now briefly elaborate on chemical pathology, a discipline I define as my life after my catholic faith and my family. Chemical Pathology: Traditional Role of the Chemical Pathologist Chemical pathology also variously known as clinical chemistry, clinical biochemistry, hospital biochemistry, biochemical medicine or medical biochemistry (Canada) was proposed by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) as "the study of the chemical aspects of human life in health and illness and ? . UNIVERSITY OF IBADAN LIBRARY the application of chemical lahatory methods to the diagnosis, control of treatment and prevention of disease" (Sans and Louis 1971). Chemical pathology is a fundamental science when it seeks to understand the physiological and biochemical processes operative in both health (normal state) and disease state. Chemical pathology becomes an applied science when analyses are conducted on various body constituents such as fluids, (blood, plasma, serum) and tissue specimens in order to provide useful infomation for clinical decisions in the diagnosis and treatment of various disorders. Sound knowledge of the working of the human body in healthy state or normal condition is essential for understanding of changes that may occur in abnormal or pathologic states. The major responsibility of the chemical pathology laboratory is the assessment of chemical changes in the body for purposes of diagnosis, therapy and prognosis (forecast) of disease. The key duty of clinical laboratory scientists who do the routine me8Smrnents consists in analyses of various chemical constituents in blood, urine and other fluids or tissues. They provide scientific data for sound clinical decision and appropriate management or treatment of disease by the clinician. Scientists and Clinicians work closely together here as in the other disciplines, with the latter focusing on the more clinical responsibilities and as liaison with physicians and surgeam Erom other clinical departments. A brief background of what is normal to understand abnormalities is probably appropriate. Chemid Composition in No& (Heaithy) State Normally, the concentrations of the chemical constituents are relatively constant, but in disease states the levels become altered, the magnitude of changes usually paralleling the degree of disease. In advanced disease states, the alterations .or abnormalities are easily detected and present not too much of an analyhcal challenge to the laboratory specialist. Early detection of organ dysfunction is much more difficult; UNIVERSITY OF IBADAN LIBRARY however, as the chemical changes are usually minor or slight and have to be differentiated from possible errors in the analytical aspect of the investigations (Kaplan and Szabo 1979). This current view may not be too different from the charter Paracelsus of Hohenheim gave scientific medicine in his acclaimed hypothesis: 'The human body is a conglomeration of '%hymical" matters, when these are deranged illness results, and naught but chymical medicines may cure the same' (Gray 2001). This essentially captures the remit of all chemical pathologists or clinical biochemists and particularly this investigator who has set himself the responsibility of advancing the mitigation of toxicity or poisoning through the mediation of the micronutrient s to testore altered physiology that leads to disease, in line with Paracelsian doctrine. Accuracy is very critical to the work in chemical pathology for the proper inkrpretation of laboratory tests. Scientists in chemical pathology indeed laboratory medicine generally, must always remember that laboratory sp imens ;m: taken from humans with a red or potential health problem and that the scientist is an important part of a highly skilled team that contributes to an evaluation of a patient's condition. As a former president of the Institute of Biomedical Science of the United Kingdom, Graham Smart once admonished, "In our pursuit of science and academic excellence, our principal consideration is that the final beneficiary must be the patient. This patient oriented ethos is the touch stone of our ' profession." Leetwahip Position in the Department of Chemid Pathology My appointment as a staff of the Department of Chemical Pathology came as a pleasant surprise and like sweet and sour event. As I had always considered my sojourn in IITA, where I spent close to one and a half decades as education and training, for indeed that essentially was what it was for me. After the defence of my Ph.D thesis, I thought it was time to go home. I then applied for a lectureship position at the UNIVERSITY OF IBADAN LIBRARY Chemical Pathology Department, University of Benin. The then head of department, Professor Israel 0.O forofuo, who is both a product of the University College Hospital (UCH)a nd the University of London, came to inquire from his colleagues in Ibadan, Professors Taylor, Salimonu and others, if I were a good person that he could employ. I was told they immediately told him that they will not release me to him and immediately put in motion the process of my employment. . Then, I was contacted to submit my CV immediately that was how I got to the University of Ibadan as a lecturer. I did not apply to U.I. from the beginning because when I saw the line up, I thought there was no space and from what I heard from others who graduated before me. Though I was later tempted with a Lecturer I position from Uniben from the back door. I am very grateful to all my teachers who considered me worthy to be employed in the department. I called it sweet and sour because at the time I was offered the appointment I was already a manager in International Institute for Tropical Agriculture (IITA) on a monthly salary of about 4436,000.00 aside from some bulk payment at the beginning of the year. Now I was offered a position of lmturer II on a salary of about P18,000.00 +. A professor's salary at this time was about W12,000.00. Though, I had always wanted to be an academic, at the time it came, the circumstances made it diff~cultt o make a decision immediately. That was when I learnt to say a prayer, which I cannot remember how it started, 'God if it is not your will put an obstacle'. I then accepted the position. Here I must say I am very grateful to late Fr. (Professor) Louis Munoz, he was one of the very few who asked me to accept without doubt and leave the rest to God. That turned out to be prophetic. All other, friends, relations etc. thought I was committing a career suicide. Just like all my class mates at Ughelli and many of my relations felt when I was accepting the offer of admission to study Medical Laboratory Science. The only personal safety valve I had in place was that if it became too rough I would emigrate. I thank God that till now there has been no cause for this. God has been very faithful. UNIVERSITY OF IBADAN LIBRARY For the Love of Chemistry I must talk about my love for chemistry which has remained unquenchable. Frobably if there were nothing chemical or chemistry in medical laboratory science or dhemical pathology 3 would have gone into some other fields. I do not know how the love of chemistry or anything chemical science grew in me, but I can trace it b the day some boobellem came to intduce some science h o k s to my class in Form two in 197 1. Two books were introduced to us 'byo ur general.s cience teacher authored by the Opwoles @tun and Philip) I think from Abeokuta Grammar School; 'Intmdwtion to Chemistry . (yellow in colour) and 'Introducfion to Physics' (red in colour). I cannot remember the full details, they were relatively 'expensive at the time, I think it was fifteen Shillings each. I got home told my mother we were asked to buy the books, she asked how much, I thought she would postponed or tell me in a week or two, or out rightly no money, instead she went to her purse and handed me the money for both books. I bought the books and found that I never wanted to put them down, particularly the one on chemistry. This is why I think whatever I have become today in the chemical sciences, I owe to my mother and the Oyewoles for the foundation they laid with their books. Till now I love chemistry and I have only come across a few people with such love, one key one is Linus Pauling, two times Nobel Laureate and Dr. b n , G oldberg (1915-1987). As Linus Pauling is so well known, I will focus on Dr. Goldberg. I found that his knowledge of chemistry and enthusiasm for its application to human health issues was like mine, the hallmark of his career. He obtained B.Sc. (Honors) chemistry from the University of Wi twatersrand, lohannesburg, South Africa, another B.Sc. degree in mathematics, M.Sc. in Physical Chemisw, D.Sc. degree in biochemistry, from the same university ,and D.Phi1. from Oxford in organic chemistry, M.A. anatomy and physiology from University of Cambridge, the Medical Bachelor and Bachelor of Medicine (M.B.B.S.) degrees from University College Hospital, (UCH) Medical School, London and an UNIVERSITY OF IBADAN LIBRARY honorary D.Sc. Degree in Pharmacy and Science from the Philadelphia College of ~h&acy and Science in Philadelphia, Pennsylvania. Goldberg contributed to the award of Nobel Prize in Chemistry to Robinson in 1947; for their study on the synthesis of stilbosteM,l. Goldberg return to South Africa to lecture in chemistry at his almamater (Wits) and became head of Biochemical Research Laboratory at the South African Institute for Medical Research. His publications focused on medical issues and the linkage between chemicals and health. My research focus as well. Goldberg later accepted a position as senior lecturer in chemical pathology in the Department of Pathology at the University of Manchester in England, and later became the Medical Research Director of Benger Labratoria Ltd, in England. His work here centered on the role of adm;i~i~tered iron in health and induced disease, galactosaemia, (WEM) and lipid and cholesterol metabolism. I adopted him as my academic mentor. He emphasized understanding of the mechanisms of toxicity of chemicals throughout his career. . Later he became the founding Director of the British Industrial Biological Research Association (BIBRA) in London. This new organization, a joint industry government effort was created to investigate mechanisms underlying toxic effect of chemicals, develop new improved toxicity tests and give advice and informati on on toxicological issues. The organization (BIBRA) was intended to be an impartial forum for improved communication between industry, government and academic personnel in addressing toxicological issues of major public health significance, issues that were emerging with increasing frequency and consciousness as we have it in Nigeria today. Later he focused on how science could address societal issues (McClellan 2011). Leon Goldberg was President of the Society of Toxicology (SOT), 1978-1979. The reason for this elahration will be clear later. Leon Goldberg's broadly charts my career roughly and remains a reference point to me in toxicology, my sub-specialty just like Linus Pauling who is also interested in micronutrients like me (recall mega-vitaminosis C, vitamin C and the common cold). UNIVERSITY OF IBADAN LIBRARY The Field of Toxicology and Micronutrient Metabolism My sub-specialization in this area arose from reading the chapter on analysis of drugs and toxic substances in the Fundamentals of Clinical Chemistry by Nobert Tietz (editor), the bible for all those majoring in Chemical Pathology in the medical laboratory science programme. I found that this chapter, and alteration of the haem biosynthetic pathway by lead, made special impact on me. Then I again (hand of God) came across an advertisement in a journal-I think it was. Jouml of Clinical Pathology, later New Scientist-- M.Sc. Degree Programme in 'Experimental Pathology (Toxicology) . at the Royal Postgraduate Medical School at Hammersmith, University of London. I applied and was given admission three times; I kept deferring, looking for scholarship, which I did not succeed in obtaining. In 1986, I was advised to apply for the Overseas Development Administration Shared Scholarship scheme (ODASS). Was assured once the school sends my name I would be awarded the scholarship. Since a classmate with lower grade got it I was very confident I would get it, having been adjudged the best and got the prize for the' Best Academic Student' in my set. I received all instructions, room allocation reading list everything except the award letter. This has been the most anxious and stressful period in my life. By the end of September 1986, I wrote and a reply came after about three weeks saying we did not send your name. No explanation was given up till date. I then embarked on the Fellowship programme in Chemical Pathology by thesis. I approached then Dr. F.A.A. (now Professor) Adeniyi as supervisor, he kindly consented and knowing my previous attempts to study toxicology advised that I work on cadmium (Cd). The Field of Toxicology Toxicology is the scientific study of poisons and poisoning. It has been defined by the Society of Toxicology (SOT)o f the United States as '%he study of the adverse effects of chemicals, physical or biological agents on living orgmi sms UNIVERSITY OF IBADAN LIBRARY and the ecosystem, including the prevention and amelioration of such adverse effects" (www.t oxicology.o rg). It is appli- cable to many areas, including the industrial, agricultural, veterinary, environmental, forensic and medical fields. In chemical pathology we employ the term toxicology to imply identification of the concentrations of poisons or biomarlcers of their effects in body fluids, tissues and other materials. It is important to understand why toxicological investigations are conducted and the'way results are usex& how poisons occur, how a diagnosis of poisoning .is made and how poisoning is txatsd. Poisoning itself may be considered as a medical condition caused by by substance (usually a chemical ) that is not usually present in the body such as methanol or is present at a much higher concentration usual e.g. iron (Re). 'Wwlley (2008) has o b e m d that we live in a chemical uloflcl, that we are composed d&micals, that an increasing awnher of chemicals found in olln bodies are persistent man- made chemicals such as pdychlcmbiphenyls (RCBs), bi-01 A or orgmcwhtorine p t k k b like DDT and that then is increasing need to emphadse safety. He noted that the major concerns of the public that ~xicologistsm ust addms .are cancer, loss of senses embracing newtoxicity, genaal debilitation (susceptibility to illness), reproductive defects (kmtogenicity) or shortened life span. These have received the attention of this investigator as will be evident during h ew me of the lecture. Toxicology today is generally recognized by the lay people as the science of poisons and poisoning. It is tempting not to overlook the recent obsecvation of Lane (2014), that 'history is full of bad intentions, ignorance and folly. - Poisoning has been part of each of these for as long as humans have lived Understanding poisons- to control them or avoid them- has therefore been an integral part of our past. As understanding of poisons progressed, a unique field of knowledge grew into the science of toxicology. As toxicology moved along this path, it evolved from harming people to ' helping them by protecting them from the adverse effects of UNIVERSITY OF IBADAN LIBRARY chemical exposure at home, in the environment and in the work place.' A toxic6logist is trained to examine and communicate the nature of the adverse effects of chemical and physical agents on human, animal and environmental health. Toxicological research examines the celluldr, biochemical and molecular mechanisms of action as well as functional effmts such as neurobehaviourai and immunological, and assesses the probability of their occurrence. A fundamental aspect of this is characterizing the relation of exposure (dose) to the response. This leads to risk assessment. Risk assessment is the quantitative estimate of the potential effects on human health and environmental significance of various types of chemical exposures that may involve pesticide residues on food, contaminants in drinking water as very recently seen in Flint, Michigan in the United States, where public water supply was heavily contaminated with lead. Others have been mercury contamination of fish in- a bay in Kyushu, Japan; ~ina&ta Disease and cadmium in the food chain also in Japan, itai itai byo (ouch ouch disease) in the Fuchu Toyama prefecture in Japan. Rkk Estimate The risk of some agent or event can be estimated as a function of the product of pro6ability (Pj of the event and the severity bf the harmfulness of the event 6r agent 0: R = P x H (Campbell 1980) From the simplest view point from Campbell's. thesis above, the risk taker may accept harm of greater severity (high value of H) only if the probability of occurrence (P) is very low. Conversely, events that m e only modestiy harmful (low value of IT) may be acceptable at higher levels of frequency or probability. From this argument, safety may be taken as a measure of acceptability of some degree of risk. Scientific risk estimation should be carPied out with the full knowledge of the action of a toxicant e.g. a carcinogenic agent as either a complete carcinogen, or as having a major UNIVERSITY OF IBADAN LIBRARY action at one or m m o f the stages of carchogenesis. Most of the data in environmental toxicology @cularl y affecting environmental chemicals and poisoning were obtained by biuassay. The extrapolation of bioassay data to human risk estimation is one of the mpst difficult problems that has faced society and its scientists and will face us for years to come as numerotis new chemicals enter the environment. To predict the khaviour of a chemical in the human from data obtained from bioassay is Eraught with a number of difficulties. Knowledge of the action of an agent with regard to toxicity and its modulating factors are impomt in toxicology and are very useful in dtigating toxic states or poisoning. The variety of pttxstirrl adverse eff6CtS and diversity of chemicals in the mvimnment make toxicology a broad science and very important science for society. Our d e t y ' s depdmce w chemicals and the need to assess pent id hamds have made toxicologists an kcmmingly impatant part of the decision-making peas (Klaaasen 2008). Toxicology has developed as a science from the study of chemicals to induce harm (the art of poisoning) to a study of chemicals in order to prevent harm (the science of pventing poisoning; antidote) and benefit to humankind' my thrust in the science. Starting from the art of poisoning, supplying and using poisons, the toxicologist now studies their mechanisms of action, develop analytical methods to identify and quantify poisons in body fluids and tissues, develop rational antidotes, establishes Bafe hits of exposure hwn mfix l ly designed and executed stud& d qmnWws and pledicts &me effects' (Lane m14). To* ~~ Toxic eff- develop from pxhibtio11a t the m o l d a r lkel p p m i n g to dted cellular W a n , e ventually giving rise to d i s ~ c e osf tissue or orgw fund011 with resulting influence on ,homeostasis that may range from mild discomfmt to death. Unfortunately, it is only the later that many accept as toxic effects that may delay seeking assistance or remedy. UNIVERSITY OF IBADAN LIBRARY Cyanide toxicity for instance occurs as follows--cyanide causes tissue hypoxia by binding to Fe*in cytochrome c ductase and inhibits electron transfer, Pesticides are chemicals used to kill pests and include organophosphate insecticides and herbicides they inhibit cholinesterase while Paraquat causes poisoning by leading to oxidative stress. Toxic Respama to Chemical Pohm by the Organism In -sing toxic responses to a toxic substance .it is important to bear in mind the concept of toxicity which involves a damaging, noxious or deleterious effect on the whole or part of a living system, which may or .may not be reversible. This is important as many people only understand poisoning to death. They do not recognize adverse effect on part of a living system as a toxic effect. A number of ways exist for an organism to respond to chemical agents. The response may be &pendent on a number of factors. Thm& many of the toxic effects of toxic agents (xenobiotics) have a biochemical basis, expression of the effect may be very di-nt (Timbrel1 2009). Tumour development may be a consequence of attack on nucEeic acids, while the other might be the birth' of an abnormal offspring as was c ~ s ob~servyed f rom. thalibmide toxicity (to be reviewed shortly). The interaction between toxic agents with normal metabolic pmames may cause a physiol~gicalr esponse such as muscle paralysis or a decrease in haemogtobin concentration, reduced glutathione (GSH) level or a tissue lesion in one organ. A covalent interaction between a xenobiotic and a normal body protein may lead to an immutl~1ogicalr esponse while it may manifest in a n o w organism or population as tissue lesion such as kidney damage (toxic nephropathy as in cadmiurn.ur inorganic mercury poisoning). Though toxic response may have an underlying biochemical basis, they are coxnmonly categorized according to the manifestation of the toxic effect. Although there is m'ognized overlap between some of the toxic responses; for the purpose of this lecture it is convenient to list them as shown in table 14x90~: UNIVERSITY OF IBADAN LIBRARY Table 1: Typw#o f To* Itespom to Xenobiotia I. Direct t& action: tisuet lesiom 2. Ihrmamb@csl,p hysiological and biochemical e k t s 3. Teratogenesis 4. Immunotuxicity 5. Mutagenesis 6. Carchgenesis Detection/Evsluatioa of Toxic R a p o m Toxic responses may be detected or evaluated in a variety of ways in an organism or population. These will be illustrated in some of the studies that will be reported shatly from the investigator's laboratory. Typically a toxic response may be the all a-no ne type that manifests as the death of the organism or e x p s d a s graded responses. These are briefly outlined here as described by TimbzeIl(2009). Death: This was previously usually &&mined by;the lethal dose 50 (IDSo)th e concentmtim of a toxic compound that kills 50% of the population. This has falling into disuse and has been largely replaced by other bioindicatm of toxicity or poisoning* . P e b o g i c a l Cruuge: .This may h expressed as tumolns or destruction of tissue as will agaiq beevident frmn some of our studies partkularly with Pb. Biochemkd Change: This was widely used in some of the studies =ported here and might involve inhibition or induction of an enzyme Q alteration in a particular .metabolic pathway as Classically seen in the hamb iosynthetic pathway altered in exposure to lead. It may also involve the appearance of an enzyme or dther markers-that may indicate leakage from a tissue or an organ due to damage as with the transaminases (ALT and AST) in liver damage as is typically seen in Paraeetmol toxicity accompanied by increase in N- acetyl benzoquinone imine (NABQUI) a toxic metabolite of Paracetamol which are indicative of pathological change or UNIVERSITY OF IBADAN LIBRARY process. Wa-e &oyed this in our study of carbon tetrachloride hduced hepatotoxicity and its amelioration by the extract of veronia amydgdina (Babalola, Anetor and Adeniyi 2001). Physwlogicd Change: This is usually a simple measure in the whole conscious organism or individual and may include change in blood pressure, body temperature or rate ,of respiration or level of cons~ioumg(T hbll2009). A&er&n or Change in No& S :- A number of markers of toxicity abound which are simple to perform and reflective of toxic response. Changes in body weight or other anthmpometric indices, food and water consumption, urine output, changes in organ weight may all be sensitive indicators of general or specific toxicity. Many studies including ours (hetor, Wanibuehi, Wk,K akehsshi, Kang and F - 2008) indicate that expehental models consume less food and lose weight after exposure to a toxicant, while increased organ weight may be an indication of a developing turnour, fluid or lipid (triglyceride) accumula- tion, hypertrophy or enzyme induction. that are commonly seen in experimental pathology or toxicology. These changes may have to be codimed by the toxicologist by chemical, biochemicd or histological examhatiom. To~cologyi s a dya;unlc subject with great irnphnce to the public and places heavy ~sgoasibilityo n practitioners; or those who cegi5ter or toxicologists*G etting a decision wrong in tuxicohgy am be assmkted with. very serbws adverse e f f h with consequent litigation (as in thali&de catastrope, no cases were seen. in those living in the U.S. because of a sharp scientht),a nd could lead to loss of vote in politics as hhas been seen with glob511 warming. Conqumtly as.t oxicdogists, we should da Rothtng without thought3 without considering the impact of w' actions on the community we; serve or the public ' p h i % thrust in us. Toxic responses may be maddated by nutxitional areans. This is where the almost dogmatic abservation by ths father of mudern toxicology, Pamcehus &at the dose solely &&mines the poison in my opinion needs revision. UNIVERSITY OF IBADAN LIBRARY NuMtronal Medicine and Chemid Exposure Requirements for essential nutrients are recognized to vary from individual to individual depending on genetic, physio- logical, life style and other influences, pahaps chemical exposure (Anetor 1997). What is adequate for one person may not be for another, probably depending on chemical exposure. illness is inevitably linked with abnormal biochemistry and an alteration in the metabolism of nutrients and their b products. Specific nutrients, phrticularly micro- nutrients and macrominerals, dietary manipulation provide a potent means of influencing body chemistry and consequently disease process. By correcting fundamental abnmalities, including altered chemical composition, one can prevent ~ertaind iseases including chemical-induced disease or alter the course of the disease for the better (better prognosis) mlonen 1990). Toxic oxygen species (Eree radicals) are common intermediates generated in altered body com- position. Toxic O q pS pecks (TOS) Toxic oxygen species are ats0 Lrnown as frae radicals or reactive oxygen species (ROS)o r reactive nitrogen species (RNS), they are chemical species ~6thon e or more unpaired electmns in their outer orbitals which make them extremely reactive and damaging to biological constituents, DNA,R NA, w i n s including enzymes 8nd htihiies; lipids, cabhydrates nucleic acids which together constitute the chemicals of life. The body @oes TOS as part of' the normal bodily processes (metaboIism), they are essential for normal bodily function, signalling and bactericidal activities, but uncuntfolled production of b radicals (excess) is damaging to the cells, tissues and organs. Free T a d i d or toxic species are among the means by which many toxic states are elicited or mechanisms of toxicity. Toxic metals such as F% and as demonstrated by our study in part exhibits this (Anetor and Adeniyi 2001a). When the generation of free radicals e x d th e bioavailability of the antidotes, antioxidants; imbalance between antioxidants and fwe radicals, a state of UNIVERSITY OF IBADAN LIBRARY oxidative stress is said to set in. Extmcellular and intracellular defence systems that protect cells against free radical toxicity are of h m s i m g importance in public health. Currently, most diseases sre linked with free radicals and their antidotes, the antioxidants including metal poisoning. Oxygen is both essential to life and poisonous: generates ROS which are chemically reactive molecules containing oxygen (Kelly 1999). Free radicals are like inner radiation, to which cellular constituents are .exposed for a long time throughout life. When the protective mechanisms by anti- oxidants are lacking (weak) bodily cells become weak or may ultimately die. To again w i a t e t oxicology it is maps appropriate to look at the chemicals of life and their amngeent, C3emid Composition and Atoms of Life In the beginning were the chemicals of life and they ensllled life. W~th the quest by man for psprity, the chemicals of afflwnce w a e i n M d a nd they d i s p i d ( over threw) the chemicals of life. This is at least in part, directly or indirectly the basis of a diqqmtionate number of all known pathologic states. AU human cells are composed of the same basic molecules and share the same fuadamntd machinery of functions such as the synthesis of protein, the means through which cells execute their functions. The cells also share a similar chemical ' composition, consisting of approximately, 70% water. About 95% of the mass of cells is made up just four types of atoms: Carbon H Y ~ P Nitrogen Oxygen These are Linked in a variety of combinations to construct h o s t a ll of the molecules of the cell. The linking of these atoms in various different ways to form proteins and nucleic acids gives the cell its complexity. The combinations of the UNIVERSITY OF IBADAN LIBRARY basic units in different ways appear to be a major principle in the life of the cell and that of the organism- what is called life (Wolpert 2009). Inside this is a collection of molecules, what has been described as a society of molecules which cany out all cellular activities, which is achieved by the work of the proteins, the most complex and varied of the molecules. Each of the thousands of the different proteins has a unique sequence of amino acids, which determine the function of the cells and behaviour. Protein function is largely determined by their interaction with other molecules, whose behaviour or structure they alter. This is an over abridged basic chemistry of the cell that can be altered by foreign compounds, chemicals, generally called xenobiotics. In the course of this lecture I shall attempt to show how this orderly arrangement of chemicals is upturned or overthrown by the chemicals of prosperity, disease and death. 'Om& CeUula e CeUula9 The German physician Rudolph-V irchow in his publication (1895) proposed a seminal concept of life: 'Every animal is a sum of vital units, each of which possesses the characteristic of life. It follows that the composition of the major organism, . the so-called individual, must be linked to the kind of social - arrangement or society, in which a number of separate existences are dependent upon one another, in such way however, that each element possesses its particular activity, and although receiving the stimulus to activity from other elements carries out its task by its own power'. This is the emergence of the society of cells. Rudolph Virchow stressed that cells came from other cells and gave the well-known . aphorism, omnis cellula e cellula (every cell from a pre- existing cell), which gave rise to the thwry of tissue formation despite gaps in our understanding of ihe ~ i s m p o f o n v c e lfl iinvdv ingthecktnkb af 3 i k Some Chemids of life: The Metals Chemicals are made up of different type of substances. Metals are among the most common chemicals on earth. UNIVERSITY OF IBADAN LIBRARY Metals play a significant role in biochemical processes of life. Several fold systems exist in the living organisms ensuring that biometals such as Fe, Cu, Zn, as well as Ca, Mg, and K find their way into cellular and subcellular compartments where they are needed by different transport systems. These transport systems can also be used by chemically closely ~ latsdm etals which elicit only toxic effects. Displacement of the chemicals of life (biologically useful) deserves scientific interest, particularly for the understanding of uptake, distribution, accumulation and disposal (exaction) of either metals (chemicals) of biological (life) or toxicological (malady) significance. Emential Versus Toxic Chemicals As the steps promoting the supply of essential metals (chemicals of life) can be investigated in the organism and the exposure of the organism (population) to toxic metals (chemicals of prosperity & malady) we ,have come to the understanding that these metals (chemicals) compete with each other. The interactions obey physico-chemical and biu- chemical laws broadly as follow: There can be impairment of availability (absorption). Transport of chemicals to target tissue can be affected (disrupted) where the essential chemical (metal) is n w and finally, the synthesis of metal pr~teinsa nd metalloenzymes which are necessary for what we call 'Life" Our understanding of life is limited, thus it is difficult to relate interactions between exogenous (toxic) chemicals and chemicals of life down to the molecular level. Need to provide more profound (sound) biochemical explanations. Currently, we have only been able to sketch limited under- standing of the complex interactions between essential metals (chemicals of life) like Cu, Fe, Zn (Essenhans et al. 1993). This is elegantly illustrated by the Fenton reaction. UNIVERSITY OF IBADAN LIBRARY The Fenton Readion The above reaction can be inhibited by caeruloplapmin. Inhibition of the Fenton mction by the protein, caerulo- plasmin and other copper complexes is a common occurrence in toxic states as shall be evident shortly (Gutteridge 1985, 1991). This is pmhcdly seen in diseases associated with industrid activities and more of these cases shall be seen in the match towards industrialization, giving rise to diseases of prosperity. Diseuses of hs- Which am the diseases of psperity? These are the diseases associated with well-being or being prosperws, a fall wt or dividend of industrial swcxss and affluence. A few of the most well-knm tue highlighted below: Itai-itai disease (a fum of cadmium-induced -malacia), exempUed with Cadmium induced bone disease. Mimmta bay Disease (mercury induced nampa&y). W d o m i d e (birth defects from Consumption of a drug, Cantergan@ to prevent morning sichess; acts largely by inhibiting mgiogenesis). All these have led to a cry to protect human health and the environment from the deleterious effects of chemicals. frotedion of Humm HeaIth and the Emvimnment Many scientists, pioneered by Rachel Carson, Osibanjo's group in our c h d t r y department in this university; d l his inaugural lecture in 2009; 'Giving the Earth a Future: Chemicals, Wastes and Pollution Risk Factor', have con- tinued to call for protection of human life and the environment. Details of the evergreen efforts made by Rachel Carson follow shortly. The Pope has also recently joined this call in his encyclical, Laudato Si' (Our Common Home) (Pope Francis 2015). UNIVERSITY OF IBADAN LIBRARY Today's World a Chemical Habitat Rachel Carson was one of the very earliest environemtnalist to recognize what is evident today, that the world is a chemical habitat. She observed the ominous trend at the time and mmdced that 'intoxicated with a sense of his own power', mankind appeared to be going farther and farther into more advanced chemical production for the destruction of himself and his world. This situation remains true today if not worse. Rachel tried ~ p e a t d l yto stimulate the interest d people with influence in society to no avail of the alarming evidence of envimnmental damage fmm widespread use of the new synthetic chemicals and other long lasting pesticides needed to improve food yield but consuming the would be consumem. This appears to be the beginning of a chain of reactions in the unending production of chemicals that is thought to increase by about 15-00a nnually (Trager 2016). The United Nations Environmental Programme CUNEp) (2012) obsemed that the exact number of chemicals on the global market is uncertain but .under the pre-registration requirement of the European Union's chemical registration, 143, 835 chemical substances have been p-registered. This is considered a misonably reliable guide to the approximate number of chemicals in commerce globally. I consider this conservative estimate. Recently, not surprisingly -this was upgraded by h u t 1 500 entering the global market annually (Tmger 2016). This massive increase in global chemical output had already been predicted and the implications for human health weze the focus of Rachel Carson's career. At the beginning of this year the annual World Economic Fonun (WEF) AT. Davos shocked the wald by the observation that by year 2050 there will be more plastics in the sea than fish and that a lot of money was being wasted on disposable plastics that are neither reused nor recycled. Though they saw the problem only from the economic point of view, it is disconcerting fbr toxiwlogists and confims what we recognize well that the sea is the final sink of all that we dispose of. This observation alludes to the pollution or poisoning of the world and confirms a local observation by Okoye (1994) from the study of fish bought from markets all over the country where they found toxic metals highly UNIVERSITY OF IBADAN LIBRARY exceeding recommended limits and concluded that Nigeria was heavily polluted We have confirmed this in some of the studies I will be. describing shortly (Anetor and Adeniyi 1999). An unrecognized source of poisoning is the growing mountains of waste, that is unsorted full of a cocktail of toxicants. What I call our waste rising against us. Fig. A: u d wasce : n common mtt. stll over the country, laden with toxicants. When we set them ablaze we are unwirtingiy poisoning ourselves. Any dijerencef rom the drinking of Azknia Hemlock by SOCMTQS? UNIVERSITY OF IBADAN LIBRARY F& 3: Release of cadmium from tyres. k ~ + i 9 9 W3 ,h el %immw a c~on virickd that the-increasing k ~ d 1 2 r rplx 6du~tjion-wda potential h a i d t o the whole biota that the .ihdi$crimidate u. ,i e'. of dhe&c& e m m w from a c&nbina&h of.ign'or&ce and greed. I share Carson's insistence that what science .con&ved and technology made UNIVERSITY OF IBADAN LIBRARY possible must be judged for its safety and benefit to the entire spectrum of life. The fruit of Carson's concern for world safety is 'Silent Spring', the pmluct of her concern and an evergreen gift to the world A book which deliberately chalteaged the wisdom of govenunent that permitted toxic chemhls to l~ released into the environment before assessment of their safety. In this immortal book, Rachel Canon, p e n t & faultless evidence of how chlorinated hydrocmbom, of which DDT was the best known at the time and organic phosphorus insecticides, altered the cellular processes of plants, animals and ultimately humans that we just examined above. This astute biologist observed that science and techn010gy. had become the handmaidens of the chemical +try's rush for profits (prosperity) and control of mrlrkets. This remains very true even today. Rachel Carson argued that the proteaion of the public from potential harm of chemicals had been disregarded without any scientific basis. This scientist whose writing and scientific report led to the introduction of the Environmental Protection Act @PA) that paved the way for .the emergeme of the Environmental Protection Agency @PA), the -type of all environmental protection agencies in the world in 1970, boldly questicmed the moral right of government to leave its citizens unprotected fmm subs- they wdd neither physically avoid nor publicly question. This ss we are seeing is callous m p c e t hat wuld only destroy ?he living world. Carson asserted in his days that one of the f u n a t d h uman rights must be the "right of the citizen to be seam in his own home against the intrusion of poisons applied by another prsmn. The mction by Carsonlhat, human W t h would ultimately reflect the environment's ills has been bome out time and time over within the 54 years since Silent Spring was f k t p ublished Scientists inchding chemical pathologists are among the hef i c iar ia of the protest by Rachel Carson of the wnbminzttim of m h ' s total environment with substances that accumulated in the tissues of plants, animals and humans and have the potential to alter the genetic stnrctum of organisms. She said 'poison one wmq of the ' environment and you end up poisoning all." UNIVERSITY OF IBADAN LIBRARY Many unethical approaches were adopted by mu1t imillion-dollar industrial chemical organizations. About a quarter of a million dollar ($250, 000), a lot of money in the 1950s was voted by the industry to d i s d t R achel Carson's research and malign her character. These industrialists as would happen in Nigeria if not worse placed economics above parriotism and the safety of the citizens. Though Carson unknown to her adversaries was battling with a rapidly metastasizing (spreading) breast cancer, she was immune to the chemical industry's effort to malign her; rather, her efforts were concentrated on survival in order to complete the book and bear witness to the truth as 'she knew it which was acknowledged by the then President of the United States. She died in 1964, two years after the publication of 'Silent Spring'. From our studies we found that exposure to chemicals cause immunosuppression (Anetor and Adeniyi 1998). At the time this was unknown, looking at the life of Rachel Carson, her frequent visits to the woods that wee heavily sprayed with insecticides; I am beginning to think that she may actually have succumbed to chemical poisoning and that her breast cancer may indeed be linked to her unintended chemical exposure. Lmking back at her health record, she developed duodenal ulcer, while on tmtment she came down with a severe case of flu that progressed to pneumonia and finally breast cancer that claimed her life at age 57 years. For imm~~~toxiwIogists, these are clinical manifestations at least in part consistent with immunosuppression unconnected at the time. For me she became a victim of a line of research she tried to p u e ; tracing the complicated link between pesticide exposure and cancer for which she wrote two chapters in Silent Spring. After Silent Spring caught the attention of Resident John F. Kennedy, he ordered fedend and state investigations into kkl Camn's clsims. Communities that had been subjected to aerial spraying of pesticides against their wish organized hemeIves against the continuation of toxic pollution. Rachel Carson was honoured posthumously with the Residential Medal of F d m in 1981 (Lear 2009). Today global contamination is a fact of modem life &ear UNIVERSITY OF IBADAN LIBRARY 2009), and Silent Spring is compelling all of us scientists and lay people alike to reevaluate our relationship to the natural world. The current Pope, Pope Francis has recently joined the league of Environmentalists by auth~ringL audato Si (On the Care of Our Common Home) (Pope Francis 2015). Specifically, the Pope lamented: Account must also be taken of the pollution produced by residue, including dangerous waste present in different areas. Each year hundreds of millions of tons of waste are generated much of it non-biodegradable, highly toxi& and radioactive, from homes, and businesses, from construction and demolition sites, from clinical, electronic and industrial sources. The earth, our home is beginning to look more like an immense pile of filth .....I ndustrial waste and chemical products utilized in cities and agricultural areas can lead to bioaccumulation in the organisms of the local population, even when levels of toxins in those places are low. Frequently no measures are taken until after people's health has been irreversibly affected. I am not surprised about this apt and timely lamentation by the Pope as he is a chemist. He has mentioned the price that will be discussed shortly below, a tall on our health that may take a tortuous pathway to evolve and may not be related to exposure to chemical poisons. The Ihunan Price With continued manufacture and release of new chemicals from industry a serious public health problem confronts mankind. This was aptly put by Raohel Carson, 'only yesterday mankind lived in fear of the scourges of smallpox, cholera, and plague that once swept nations before them. Now our major concern is no longer with disease organisms that UNIVERSITY OF IBADAN LIBRARY once were omnipresent; sanitation, better living conditions, and new drugs have given us a high degree of control over infectious disease. Today we are concerned with a different kind of hazard that lurks in the environment- a hazard we ourselves have introduced into our world as our w= ay of life has evolved (Carson 2002). d+. ; r i w- Fig. 5: I n f d b r w t feeding mother and child. One of the greatest dangers of chemicals is that Anute causes produce mighty effects; ' effects often apparently unrelated to the cause, appearing in in a part of the body remote from the area or port of entry of the exposure (Carson 2002). By the end of the 1 9 c~ent ury, about half a dozen sources of industrial carcinogens were known in the 2 0 c~en tury this was increased to countless new carcinogens (cancer causing chemicals) and to bring the general population into intimate contact with these chemicals. In the less than two centuries since the seminal observation of Percival Pott ' (1 775), the environmental situation has changed dramatically' No longer are exposures to dangerous chemicals occupational alone, they have entered the environment of every one- even of children as yet unborn. It is hardly surprising, therefore, that we are now aware of an alanning increase in malignant disease,' 1:4 (one in every four) (Carson 2002). It is painful UNIVERSITY OF IBADAN LIBRARY that this warrior against chemical poisons and connection to cancer herself became a victim of cancer. Today the situation is much worse there are more cancer cases in the industrializing countries and a larger number of cancer deaths are from the developing countries. Yes, we welcome economic progress but this has to be balanced with implications for health. This was given only very the minimum attention in the classic newpathy, Minamata bay disease* Ecodc.Progressa nd C?hedmlE xpawe: The Story of Mimmata Bay - Poisdning by the chemical, mercury, (Hg) in a Chisso Plastic Plant in the Souhedy Kyushu sea town of Minamata in Jam, w& first manifest& by the strange dance of cats on the streets, a strange 'damt, which at times ended in their collapse and death. Mnmata was a madest fishing village in the d y 19 50s. The wonisomestory actually began in #he 193Qs. The town was k m g to shed its heritage as a poor farming and fwhing community. The w e b m e ecunamic up- liftment was facilitated by Chisso Corporation. The corporation had been an integral part of the local economy in the early 1Ws, it comeneed the manufacture d aceraldehyde for the pduction d plastics; Hg was a component used in this pmcas r~eleas~ing mercury zs a bi- product. It took many decades to t he eause due to mercury poisoning; part of methyl men;.ury (@]E3-Hfg) that enters the food chain. Residents that were largely fisher men depend heavily on fish and shell fish to meet their protein requirement. At the end of World. WW II (VVW II) the production of aceMdehyde we increased wih associated economic boom and a t k m b t great appreciation of the improved socioeconomic smw and Mestyle j.9tchiko tW@$ A h ~ ~ r simultm~usly,f ishes weie floating in sea in Minamata Bay. Cats also w n h u e to exhibit bizmz behaviour, falling into the sea and dying (cat suicides). About the same &me, similar behavim began to be observed in humans; stumbling while walking with inability to write or button up clothes. Problem with hearing and swallowing and UNIVERSITY OF IBADAN LIBRARY peontrolled trembling (Parkinson' s syndrome) was also @%serve(dC larkson 1981,1987; 1991) About 1956, a clear epidemic was evident and fear was Ppable along with confusion. Two candidate causes were pmdately admissible; viml brain inflammation, syphilis. were ataxia or alcoholism; they were also called dancing disease" or "strange disease". Some physiological eects were the loss of motor control (paralyzed and mntorted bodies), there was also inability to keep afloat or maintain balance in water on falling from a boat. The patients were also unable to put on sandals by themselves, walk p p e r i y or understand others. Men also performed what was &led "craze dance", salivated or convulsed, t k th eir skin with their own finger nails a condition similar to bsch Myhan's syndrome. One .member of a given family may be the first to be affected probably the husband, then the wife md others. Scientific hvatigation In nearly all the classic cases of metal poisoning all of which were first reported from J a p ; I tai, ita disease, and Minamata disease the power of science ww brought to bmr Cmful s ~ i e n ~stlcfd ies.;revealed that the disease arose h m t oxic metd risoning (mercury poisoning) caused by eating fish and &&lfish contaminated by mercury from Chisso Plant was mpnsibk. Dr. Hajime Husokawa who conducted the investigations on cats at the Chisso Company Hospital, provided evidence directly linking acetaldehyde waste water caused the disease. The key experiment showing that cats developed the characteristic disease when administered effluent water from the polluting factory was unfortunately suppressed by the spbnsoring company an8 details were only made available after a delay of about four decades (40 years); extreme case of confiict of interest. About 100 patients were first identified with a mortality of 20. The community's way of life in Minamata itself had been poisoned Poison from the food from the sea also flowed into the blood of the community (Eto.et al. 2001). This remains a challenge to the UNIVERSITY OF IBADAN LIBRARY present day investigator. It also calls for greater need for government to listen to scientists, especial1 y toxicologists not just wait for fire brigade approach when what could have been averted at the budding stage explodes. We for instance warned about wide spread lead poisoning on the African continent before it blew open in Zamfm State (Anetor and Adeniyi 2000a). I have described the Minamata episode to some &tail because of the lessons they hold for us. We shall now report some of the key ones of the research activities in the toxicology unit of our department. * Fig. 6: Mercury cycle in the environment. Source: Liu et al. (U108) Research at the Toxicology and Micronutrient Metabolism Unit, Department of Chemid Pathology One of the very early studies we conducted in our toxicology unit was on cadmium (Cd). The investigation of Cd in smokers along with other toxicants such as lead are also described, suggesting overthrow of the chemicals of life by those of prosperity, disease and death. UNIVERSITY OF IBADAN LIBRARY Overthrow of the C h e m i d of Lie by the Chemicals of Prosperity, Disease and Death= Social Toxicants and Cometi- Carimium Toxicity in Cigarette Smokers Cadmium is a. ubiquitous chemical that is only poorly excreted with a long biological half-life (lnalp proximately 20-30 years. Cadmium though poorly heralded is especially dangerous; it is cumulative and bioaccumulates in tissues. It has consequent1y gained recognition in scientific cycles not only in occupational environment but also in environmental pollution. Cadmium is poorly absorbed in the gastrointestinal tract (< 8%) in contrast it is more strongly absorbed through the respiratory tract; inhaled Cd readily penetrates the alveolar epithelial and entea the blood stream. This pathway is particularly an important route for the delivery of cadmium to cigarette smokers; cigarette is rich in cadmium (Lewis et al. 1972). An important biochemical characteristic of- Cd is that it is taken up by the epithelial cells where ~ d ' +i s a molecular 'mimic' of ca2+a nd enters the cell through calcium channel, a well-known important element. ~ & u m is a serious nephmtoxicant (damaging to the kidney) and also impairs bone metabolism. This arises from the tobacco leafy plant which contains substantial amounts of cadmium (Goyer 1997). Consequently, cigarette smokers have many fold Cd *intake (Goyer 1997). This can be exercabated by micro- nutrient deficiencies which promote greater intake and toxicity of Cd (Bremmer 1978; Goyer 1995). Cadmium interacts metabolically with three essential metals; calcium, iron and zinc, two of which play key roles in osteogenesis (Goyer 1997). Even in small amounts Cd causes significant organ damage. Cadmium deposited in osteoid (bone) tissue interferes with - calcification, decalcification and bone modelling (Bhattacharya et al. 1978). Itai-Itai disease (translated to it hurts, it hurts for want of name), a bone disease first reported in the Fuchu-Toyama Prefecture of Japan is thought to be due to excessive exposure to Cd in the presence of nutritional deficiencies (Tsuchi ya 1969; WHO 1995). Nutritional deficiencies are quite common in this environment. Some controversies still exist as to whether the primary effect of Cd UNIVERSITY OF IBADAN LIBRARY on Ca metabolism is a consequence of effect on tissue or to its effect on bone. It is remarkable that a population in America with a similar level of exposure but with optimum nutritional status did not come down with the 'disease. Concern about the health effects of cadmium has been largely restricted to its possible causal links to hypertension and kidney disease (Lewis et al. 1972; Schroder 1976). The possibility that interaction between cadmium and calcium in bone may wwlt in disorders of bone rqetabolism is seldom considered. MTlrh the growing population of smokers in most developing countries, including Nigeria (Mackay 1994), cadmium may constitute a significant health problem in a significant segment of the population with implications for bone disease. This investigation was conducted to examine the interaction between Cd status and bone metabohsm and the possible risk of cadmium-induced osteopathy (bone disease) in Nigerian cigarette smokers. Our data (Anetor and Adeniyi 2002) (table 1) suggest the existence of both oxidative stress and impaired calcium and bone metabolism which may heighten the risk of h e di sease such as ostwmalacia and premature & set of osteoporosis in Nigerian cigarette smokers, Table 1: Semm Total CaI- Lo& Calcium, Inorganic Phosphb, Totd Proteh, Albumin and AIkaline Pbqhatase Activity in Smokers and Nan-smokers . Prcrameters Smokers Nom m k e r s rct" %" Total cddum 2.30 k 0.02 2.40 k 0.03 2.81 0.05 T. glob. (g.1OOml) 3.0 k 0.009 3.5k0.11 . 3.47 c 0.001 Values are mean & SEM Soume: hetor and Adeaiyi (2001a) Cadmium and Risk of Prosfate Cancer in CiguteEte Smokers After the previous studies associating Cd with bone disease, heart disease and cancer risk, we examined the possible relationship of Cd with cancer that is common in men, prostate cancer. Prostate cancer is a major health problem in both the industrialized and developing countries. It is the most frequently diagnosed male cancer and the second most common cause of cancer death among men accounting for 29% of all new cases of cancer (Jemal et al. 2007). The aetiology of human prostate cancer is complex and poorly understood. Prostate cancer is known to be more aggressive in smokers. The explanation for this is uncertain. Cadmium aside from being a substantial constituent of cigarette smoke UNIVERSITY OF IBADAN LIBRARY Wtarug and Moore 2004) is regarded as a human carcinogen md the level .is rising in the developing countries (Bakshi et 4 2008). Though Cd has been associated with lung cancer, the dationship with prostate cancer is less clear. Cd is also an mtagonist of Zn, a micronutrient abundant in the prostate @and. The relationship or ratio of Zn to Cd and its implica- h s fo r risk of prostate cancer in cigarette smokers remains rmexplored. To clarify the possible' role of alteration on DNA wair pathways and prostate mcinogenesis we examined this ratio and related biochemical correlates in active cigarette smokers. In this report, we evaluated the individual and combined effects of Cd-Zn ratio as a possible predictive biomarker of the risk of prostate cancer in cigarette smoker. We reported (Anetor, Ajose, Anetor et al. 2008) that Zn: Cd ratio was significantly reduced @ 4.001), implying high cadmium: zinc ratio (tables 3 & 4). This ratio was 4.5 fold that of non-smokers. The key plasma proteins and broad sub- fractions, albumin and total globulins were all significantly reduced ( p 4 . 0 01 ) . K+*r eflecting potassium channel kinetics, was significantly higher (@.05), unlike Mg which was significantly reduced in smokers than in non-smokers (p4.01). We observed that altered Zn status, culminating in high Cd: Zn ratio appears to be the central factor in smokers, leading to oxidative stress, DNA damage, mutation, impaired DNA repair mechanisms, p53 expression, impaired signal bansduction (a1 tered ca2X), angiogenic effect of Cu, and impaired vitamin A metabolism. These pathp hysiological effects may all converge in the risk of the carcinogenic process, suggesting high Cd: Zn ratio as the critical determinant of the risk of prostate cancer in smokers and possibly a biomarker of susceptibility to the disease. UNIVERSITY OF IBADAN LIBRARY Table 3: Serum Cd, Zn, Cu, Mg, K*,a nd Fe LRveIts in Smuken and Non-smokers Smokers Non-Smokers .. Values are mean * SEM Table 4: Serum Calcium, Total Protein, Abumin, Total GbbuIins, A l m e P hwphatase in Cigarette Smokers and Nun-smokers Smokers Non-Smokers Cn=sS) (d l ) P T.Chol, (d)14 9,O k 6.2 161 &,05 T. protein (@I)72 .0 * 0.7 78.0 0.80 ~ h l m i n 41.0 & 0.5 T. globulin (&I) 30.0 k 0.90 Alp 25.0 * 0.87 Cd :Z n ratio Chemical-Induced Female Baldness (Alopecia) (Hair Relaxer Induced Alopecia) Another toxicant we examined in this field is the aspect of cosmetic toxicology, one of the fastest growing aspects of which is the use of hair relaxer among women and the scalp trauma that it elicits by way of female baldness. The discovery in the 19th century of alkaline hair relaxers by Garrett Augustus Morgan paved the way for the use of this agent to alter the basic structure of the hair shaft. A hair relaxer is applied to make hair less curly, and its consistent periodic usage causes the hair to maintain a non-curly appearance. The active ingredient of many relaxers is a strong alkali, although some brands contain ammonium thio- glycolate. Misuse or excessive usage has been reported to UNIVERSITY OF IBADAN LIBRARY cause hair breakage or alopecia in some groups of women (Borovicka 2009). That this occurs only in certain individuals and not all users suggests that there might be some other underlying causes. Apart from environmental causes such as hair relaxer type or other chemical agents, congenital, infectious, autoimmune, or nutritional causes have also been considemi but remain u n ~ o l v e d ,W e studied women of African-descent who use hair relaxing products for hair strengthening purposes and develop lingering non-resolving alopecia. Three female populations; A, B & C as follow; early users and late users with alopecia and users without alopecia respectively were studied. W e a ttempted to exclude as far as possible confounders in our study population. Figure 7 shows some women with typical non-resolving alopecia. Altered serum Zn alone was found to be the probable cause of alopecia in early users and long-time users (table 5). We speculated that the women may probably have had a lower Zn level compared to the general population before exposure. We recommend (Iyanda, Anetor and Oparinde 2911) that assessment of Zn level in users of hair relaxer may be an advisable risk assessment strategy and women at risk eould be advised to take zinc supplement (even before mmmencement) as an antidote. Fig. 7: ~ o m &w ith typical lingering or non-resolving a i o ~ i a . UNIVERSITY OF IBADAN LIBRARY Table 5: Age, Duration of Exposure and Serum hvels of selected Minerals and V l h m h in two Categorim of Alopecia Subjects and Controls - . Group A Group B Group C F-v alue P-v alue @mow) 12.1 1 * 0.37 11.96 k 0.90 14.27 * 0.34 4.77 0.014* Cu (mom) IS. 85 * 0.69 14.55iO.66 15.71M.82 0.962 0.390 Mg 0.794.05 0.7M.M 0.704.05 1.091 0.345 Mn ( ~ v L ) 114.3*72 11 2.86s5.22 I08.546.23 0.ZO 0.780 Vit. A (pmdL) 1.914.17 1 . 9 M .1 4 2.03M.11 ' 0,194 0.824 v i a (~unoyL) 15.78~1.39 18.14.39 16.01&1.16 0.801 0.455 Age@-) ' 41.5k1.9 42.9d.2 40.h1.7 0.259 0.773 Alopecia duration (yeam) 14.3x1.5 8.1s0.90 - - -- -- -. - .- . - - - . - - - - Val- are M a n k SEM *Significantly different UNIVERSITY OF IBADAN LIBRARY UNIVERSITY OF IBADAN LIBRARY different manifestation that may not be physical; neurological defects, increased disease susceptibility, shortened lifespan etc. Some of our studies point to this possibility as in iron supplementation when not indicated. Iron poisoning may be unwittingly precipitated with manifestations reminiscent of thalidomide toxicity. The role of Cu in angiogenesis is unknown in this catastrophe. What was the Cu level or caerulo-plasmin level like in the mothers of thalidomide babies/ patients? Could it have been a promoter in this disorder? F i i . R TW&mi& anbryoptby in m-human pfimtes (Rbsrrs monkey), After W i n ( 1972) Th&dOIkG& eE&?iwpethy hW Rhesus 3XiOFkey. kft, IIOO-dny @Idm onkey %h tma&nmt of the MBEher with a single dme of 30 mgkg Widomide on day 26 sf gestation: rig& m m d lW &y old fetus. %#me: Wilson, 3.G. (1972) Abmnmlit%eso f intrauterine &vetopnmt in mn- human primes, Acta hdcmhol. S q 4 I%, 261-292, with permission of the Swkq ofthe Eumpmn Journal a / E & ~ ~ ~ h i o g y UNIVERSITY OF IBADAN LIBRARY & 9: Sorratts cummitting suieidG by --uming tbe ~the*an state W n , AfW T i B (t m] Unknown to us we may also be committing suicide in little bits. This is p a c t i d l y what we do every day to ourselves in today's chem'ldal wdd, only that they are in small doses that we miei hmweqmnti:at. But for the large functional mmve of rrmost wpig and systems in the body and may be endawed -e -biotic metdmIic system, which is gmetidly & l i a~nd ~ mc epbility is variable. N&@-g; minor mtablic defects or lesions may build up to a cIimax when the toxic burden perhaps - potentiated by hidden hunger (mimunutrient deficiency d h d m , MDDS) makes a victim s w & . Recently, toxi~xpIa@~~.havce alled for a rethinking of risk assessment, givhg synergistic eflwts of low -dose to be a pmmthl permissive factor foa- disease especially cancer (Colacci and Kleinsmw 2015). Ckupathna! E~pcrsare-anPd uboniog I shall now pmwnt some of the studies in occupational exposure that unearth the combat between the chemicals of Hfe and the chemicals of prosperity to be followed by those UNIVERSITY OF IBADAN LIBRARY involving our mechanistic search for an antidote for a poisoned and hunely world Toxicology of Lead: A Prime Environmental Pollutant and Toxicant Lead is one of the oldest chemical poisons known. A lot of scientific efforts have gone into its elimination or reduction in the environment. Yet it remains with us today. A reminder.is needed that the weight of Pb adds up and may manifest later in life depending on the metabolic equation. Fig. 10: B d e n of led - prime environmental pollutant. After Spivey (2007) Immunotaxicity of Lead (Lead-Induced h m o - supra9sion) The immune system (fig. 11) in any population is very important for the protection of that population. This is particularly more important understandably in a setting like ours where infectious diseases are endemic and the need for an intact and competent immune system is obvious. There has UNIVERSITY OF IBADAN LIBRARY $en increasing concern about the effects of occupational and svironmental pollutants on immune function; the most liaportani of the pollutants is Pb (Faith et al. 1979). Lead and ibp compounds have been shown to induce immuno- oppression or decreased host resistance to infectious agents m experimental models (Hemphill et al. 197 1; DeBruin 197 1; h n e t al. 1979). The possible effect of the pervasive effect d lead on the immune system was considered of sufficient hprtance 10 receive scientific attention especially that bnsistent data existed in the few and scattered reports in & literature. We were driven by the increasing abundance of in the Nigerian environment, a consequence of pgressive industrialization which demands that we establish b degree of human risk. It is desirable to h o w if the risk is $significant or substantial in order to provide an intelligent eecupational and environmental health policy. We examined lndices of both cell mediated immunity (CMI) and humoral Immunity (HMI) and a key index of micronutrient status, vitamin C. (Anetor and Adeniyi 1998): Total lymphocyte count (TLC), total globulin, IgA, IgG, IgM, CRP and related b~ bad level (table 6). kg. 11: The immune system in health and disease: A continuum, After Kaminski et aL (2008) UNIVERSITY OF IBADAN LIBRARY Table 6= Blood Lead Level aud Urinary Ascorbate LRvd ln Lead Workem and Control Lead Wotkers ControIs t P Blad l d le vel (Wdl) S6.3k0.95 30.4kl.4 18.91 0.001 Values are mean rt S. E. M. I Table 7: lmmunoIogkd Indices in h a d Workers snd Controls Vdues are means * S. E.M. After A m o r and Adeni y i (1998) n = numbeT of subjects Data suggesting suppression of both humoral a d c ell mediated immunity with associated inflammation. After Anetor and Adeni y i ( 1 998) Table 8: Cormlation M e e n B bwI L m d b e l s a rrd IgA 4n Lead water Blood lead level was significantly higher in the lead wurktxs than in controls (P< 0. 001) { M e 6). The indices ut immunological indices were all rducd, except for total globulin and CRP that were raised suggesting inflammation, while the d u c t i o ~in~ th e other indices of immune function are suggestive of immunosuppression (depressed immune function) (table 7). The inverse codation of IgA with blood UNIVERSITY OF IBADAN LIBRARY lea& h e 1i s particularly noteworthy for its implication for gastroi nterstinal tract (GlT) and respiratory disorders (table 8). These data suggest that lead workers may be at greater risk of increased sumptibiiity to infectious diseases, inflammatory disorders and very importantly cancer. it is on record that we were among the first investigators to link lead with risk of cancer (Anetor and Adeniyi 1998). Inorganic lead is now considered a promoter of cancer (Kwong 2013). This may in part be a contributor to the upsurge in cancer rates in the economically disadvantaged communities. This port appears to provide scientific explanations for the symptoms that patients always presented with; absenkism from work, un-subsiding coryza, prolonged diarrfroea and increased susceptibility to disease. ZRad is described as the most studied of dl toxic substances (Goyer 1993) and remains important and relevant today. Due to its wide spread application in the industry and its massive application as -additive to gasoline (leaded gasoline), maethyl-lead (TI%) which has been described as the mistake of the 20& century (Shy 1990) and largely phased out now in most developed countries, hopefully also in Nigeria. The great public health significance of exposure of the public to lead; reduced cognition, anaemia, depressed d immune hktion and attendant i n d su sceptibility to disease, systemic inflammation and implications in wprductive disorders in both male and female. Indeed, lead is strongly belieid to be responsible for the fall of the Roman Empire due to reduced fertility (Gilfillan 1965; Watson and Proudfoot 2001; Timbrell2009). A view strongly m ~by the t =pat of~ Carlsen e t al. (1992) that fertility has been on the decline (increase in infertility) after a %year study. These disturbing scientific wrts led us to design comprehensive experimental. and nonexperimental studies into lead with a number of sub-themes to provide sound scientific basis for policy formulation and regulatory decisions. UNIVERSITY OF IBADAN LIBRARY One of the first studies was to explore the magnitude of the problem of lead poisoning (plumbism, satumism) in Nigeria This first study was divided into two phases. In the phase I which investigated occupationally exposed individuals, 137 subjects comprising of 86 exposed and 51 unexposed (control) participants. The occupationally exposed participants were largely drawn from the occupatiorrs represented in tible 9 below .. Table 9: Dhtributio~o~f h a d W orkers in Phase 1S tudy Number of participants Batteu plant A 17 Source: Adeniyi and Anetor (1999) The control, unexposed participants were essentially indoor administrative workers non-occupationally exposed to lead. They were sex and age matched as well as in socioeconomic status. Consumers of alcohol and users of cigarettes were careNly noted. In the second phase of the study, a total of 880 participants who were not occupationally exposed to lead were selected from three sites in Southwest, Nigeria (Iseyin, 115, Shaki, 280 and Ogbomosho, 284). From Sokoto, North- West, Nigeria, 201 participants were recruited. It is remark- able that this latter location bothers with Zamfara state now internationally recognized for its p f dan d unptxdmted episode of lead poisoning {Anetoa et at. m16) in the environmentally exposed individds* The chmacteaistiics of the subjects and blood lead levels, the biomarker of lead exposure and poisoning are shown in table 10. UNIVERSITY OF IBADAN LIBRARY Table f 0: Bllood h a d Leveis (PbB) in Lead Workers, ControIs and &cupationally U m P d c i p n t s Numberof Age B l d I& level subjects (y&m) Wfa Lead-worlrers 86 24.8 * 5.8 56.3 0.95 (26-9 7) Control subjects 51 25.3k4.7 30.1&1.47* (10-58) Other unexpod 880 25.8 * 6.3 28.8 * 1.22* - subjects (15-63) All values are mean * S.D with mge in parenthesis Compared with lead-workers, values were significantly lower (P < 0.001) in the general population. The data from these two- phased studies are very instructive; occupationally exposed participants exhibited significantly higher PbB than in controls and environmentally exposed participants (P < 0.00 1) (table 10). Remarkably 95.3% of the exposed subjects had PbB gxeater than 40vg/dl, the universal upper limit of acceptable PbB in lead workers. About 70% had PbB greater than 55pg/dl, a level considered indicative of excessive exposure. Additionally, about 40% of the lead workers had PbB of 60pg/dl or greater, a level indicative of the need to remove the individuals from further exposure. Only about 5% had PbB below 40pg/dI. Though the main thrust of this investigation was to examine the levels in lead workers relative to those of controls, the results in the control, (apparently healthy participants) are very disturbing. The data from the lead workem though unsurprisingly demonstrate excessive exposure and toxicity (poisoning), they are consistent with earlier repats from similar populations all over the world. Only about 18% had blood lead levels falling within commonly acceptable PbB, about 7% of controls (occupationally unexposed) had PbB within the range indicative of moderate toxicity; over 8% had PbB above levels acceptable in occupational exposure, while 4% fell within range indicative of severe exposure. Data from the UNIVERSITY OF IBADAN LIBRARY unexposed ( g e n d ) population are similar to those of control I for the lead workers, with very similar distribution. Taken together the data suggest lead poisoning of high magnitude from both environmental and occupational exposure. These have far reaching implications that will be highlighted in subsequent studies. The data call for measures to reduce exposure. This probably in part informed the intervention of the.W orld Bank in reducing blood lead level in Sub-Saharan Africa by phasing out lead from gasoline, a 'project in which I was a Men* of the National Committee head by Eng. Arninu Jdal. The paper I presented at the national conference has been adopted as one of the Working papers of the World Bank Working Paper Number 6 (Anetm 2001) (fig. 12). E"ig. 12: National committee on the phaseout of Leaded gasoline in Nigeria World Bank W d g P aper Nuder 6. UNIVERSITY OF IBADAN LIBRARY Table 11: Blood kd XRveIs in lead Workers in Nigeria and in Advanced and Emergimg Fmnomies cmbrg PbB (WdI) Investi ga t o r(s) Unlted States 37.1 Gartise et. d (1982) U, K, 39.4 a Fesguson(1986) Korea 45.7 ' Kim et. al. (1995) Jamaim 33.0 Matten et. al. (1989) Nigeria 56.3 * 0.95 Adeniyi and Anetor (1999) The lead level in our occupatronal cohort falls within levels indicative of severe lead poisoning and may be reflective of a combination of two factors; lack of regulation and two the high lead level in our gasoline at the time of our study (Commencement of phase out was in 2003). Later reports from our laboratory (Anetor et al. 2007b) strongly favour the latter. Lead content of Nigeria' gasoline was one of the highest in the world (Arah 1985) and contributed to the substantial magnitude of lead poisoning in Nigeria (Adeniyi and Anetor 1999). The periodic studies of the National Health and Nutrition Examination Survey (NHANES) of the United States have provided a useful surveillance programme. It identifies significant trends in exposure to lead. The NHANES II (1976-1980) determined PbB in over 9,000 Americans and demonstrated that 37% population-wide decrease in lead levels paralleled a 55% decrease in the use of leaded gasoline (Annest et al. 1983). The data were useful in further attempts to reduce tetraethyl lead in petrol. The NHANES III (1988 - 1994) identified high-risk populations for excessive exposure to Pb, in the process providing improved strategies for reducing lead toxicity. Table 12 shows the progressive lowering of blood lead level by the Centres for Disease control and Prevention (CDC) leading the way for other nations including Nigeria. UNIVERSITY OF IBADAN LIBRARY Table 12: CDC Elevated PbB Benchmarks by Year Year CDC- elevated benchmark (wdl) Pre- 1970 (adults and &&en) 60 Source: CDC (2012) and Richadson (2005) Indicators of Metabolic Poisoning: Implications for Early Detection Lead is poisonous without any useful biological function in the organism. It however has excellent physicochernical properties that are very useful in a wide range of industrial activities and occupations that are extremely beneficial to man (Zielhuis 1983). From these occupational activities lead in the form of dust or fumes gains access into the human environment and into the human body culminating in lead poisoning (Landrigan 1990). Acute clinical lead poisoning is easily recognized; in contrast prolonged chronic exposure is insidious, The biochemical manifestations of such an exposure represent what is called metabolic poisoning. Metabolic (sub-clinical) poisoning is considered to exist when it is possible to detect alterations in metabolism secondary to lead absorption. Clinical lead poisoning on the other hand is diagnosed when absorbed lead produces signs and symptoms that are obvious to the patient or physician. Metabolic poisoning can exist without clinical poisoning but not the converse. Owing to the undesirable severe consequences of clinical lead poisoning it is important to investigate the possibility of metabolic poisoning to provide a basis to avert clinical poisoning. In this study we investigated a cohort of 80 lead workers and unexposed individuals. The workers were classified into low, moderate and high exposure categories according to prevailing air lead level in the work environment (NIOSH 1978). Our findings confirm the UNIVERSITY OF IB DAN LIBRARY intimate metaboKc pathways in which lead ions (Pb*) and calcium ions (Ca++) participate. Pb++ have been shown to compete with Ca++ for uptake by Ca++ channels (Simons and Porock 1987) while ~ b *als o block ~ a e*ff lux from the cells by substituting for ~ a - - NAaT P pump (Simons 1986). The hypocalcaemia associated with high BLL in our report (Anetor et al. 1999) may be explained by the mechanisms above. Importantly, we think it is reasonable to suggest that cohorts who are exposed to lead and whose intake of calcium rich fmds are considered to be borderline or reduced ; levels of total and ionised calcium, reduced cdcitriol (1,25 (OH)$ and raised uric acid level may be some of the biochemical indicators of metabolic poisoning (table 13). We provided evidence that comborate the renal excretion of uric acid and the biosynthesis of 1, 25 (OH)D occur at the same site, the proximal convoluted tubule (PCT)( Ball and Sorensen 1969; Goyer and Rhyne 1973; Brunette et al. 1978). Our findings provide useful- information .t hat the combination of hy pocdcaemia, hy peruricaemia, decreased calcitriol level are reliable biochemical indicators of metabolic poisoning of lead particularly in nutritionally disadvantaged communities which may serve as basis of early warning signs of impending clinical lead poisoning. This would have been useful in the early detection of the lead poisoning in Zamfara state were we a prepared nation. UNIVERSITY OF IBADAN LIBRARY Tabb 13; Biochemical hdiees of (parameters) in Lead Workers and Control Lead Workers ControIs t P-values B l d l ead ()~moyI) 2.72 0.M 1.47 0.07 18.91 < 0.001 Total Ca (mmoV1) 2.22 i0. 02 2.31 * 0.02 2.6 < 0.01 Ionised aktum (mmVI) 0.87 * 0.001 0.99 * 0.01 6.67 < 0.001 Inorg. Phos. (mmoY1) 1.18 k0.003 -1.21k 0.029 1.5 > 0.05 Total Prot. (%/I) 82 k 5.6 75 & 1.6 1.05 > 0.05 Albumin @) 44 * 0.50 44 * 0.50 0.56 > 0.05 Uric add (mmoV1) 311 * 16.6 204 i 11.3 5.28 < 0.001 lJ5.( OHjaD3 54.6 * 21.3 72.8 k 28.4 8.88 < 0,001 % with Ca level < 2 (mawV1) 19 4 - Values are Mtm k +EM > 0.05 = not significantly different < 0.01 = significantly different < 0.001 = very highly significantly different UNIVERSITY OF IBADAN LIBRARY Nutritionally Essential Metals and Lead Poisoning The relationship between essential and toxic metals in nutritionally compromised communities and the modulation of toxicity is often ignored. Yet scattered reports suggest this may have beneficial effects (Cerkwleski and Forbes 1976; Papaioannou et al. 1978). Such a study may reveal the level of risk or protection. We evaluated the relationship between Pb and nutritionally essential biometals; Cu, Fe, Zn in Pb lead workers, comprising of, welderdpanel beaters, mechanics, painters, battery workers and printers. The Pb workers were classified according to exposure category based on the (NIOSH 1978) standard prevailing air lead levels, PbA; low, moderate & high. Controls were selected from individuals not known to be occupationally exposed to lead or by hobby. W e found significantly higher blood Pb level in lead workers than in controls (p < 0.001). The levels of the nutritional metals, Cu and Zn were atso significantly higher in Pb workers than in controls, Serum Fe level was not significantly raised (table 14). Among the striking findings in this study were that the blood lead levels in all 3 exposure categories were all significantly higher than that of the controls (p< 0.001) in alI cases. Serum Fe level was significantly lower in the low exposure category than in the moderate and severe exposure categories (tables 14- 17 ).Very interesting1 y , the low exposure category with the lowest Fe level exhibited the highest blood lead level. Also remarkable is that Zn level was significantly higher in the severe exposure category than in the low and moderate categories (tables 14, 15 & 17). The low exposure category with the lowest Zn and Fe levels also exhibited the highest blood lead level; additive effect (Anetor, Adeniyi and Taylor 200 1). These results appear to strong1y suggest that the dose alone of Paracelsus may not solely determine the pisan and that the levels of nutritionally essential biometals may be protective (have antidotal effect) against lead poisoning and that the contrast, very common in many developing (industrializing) countries may put the population at greater risk of lead (metal) poisoning. UNIVERSITY OF IBADAN LIBRARY Table 14: Blood Lead (PbB) Level, Semm Cu, Fe, 2511 and C-reactive Protein (CRP)L evels in Lead Workers and Controls Lead workers Controls t P PbB (pmol/L) 2.72 k 0.05 1- 47& 0.07 18-91 < 0.001 C- reactive protein (mgL) 6,O k 0.3 5.0 k 0.3 2.56 < 0.01 Table 15: Serum Levels of Cu, Fe, and Zn according to Egposure categorg. Low Maderate High (wow) 19.36 & 1.27 16.14 k 1.38 19.36 3: 0.64 a = Low exposure category versus moderate category b= Moderate versus high exposure categories Table 16: Blood Lead (PbB)L evels according to Exposure Categories and in Controls Ex Cat o n Low 8 2.92 k 0.01 1.77a > 0.05 Moderate 34 2.64 k 0.02 1. 19b mgh 44 2.75 k 0.07 Control 5 1 1- 47 & 0.07 c 0.001 a= h w e xposure category versus moderate exposure category b=Moderate versus high exposure categories Table 17: Serum Zinc LRvels in the Major Occupational Gmups Panel b a t e d Meehaoics Bwaotrtkeerrys Painters wdders(n=30) (-17) (n=ll) ( n= 15) zn 145 * 2.23 87 k 1.58 104 A 3.97 92 * 1.88 T - - 4.19 0.28 2.73 P - < 0.001 < 0.05 U.05 UNIVERSITY OF IBADAN LIBRARY Table 19: Seminal Fidd Volume, Motility, Morphology 4T otal Sperm Couot in Lead Workers % Lead Workers Controls t P Total sperm count 61.4 * 5.0 (xlo6/ m3) Normal 65.9 c 3.2 morphology Seminal fluid 2.9 2 0.40 volume (em') . . . . . . . -- Values are means & S.D. Table 20: Correlation between h d an d B i e e m i d hametem und between h a d and Semen Characteristics 1: pvalue PbB vs winmy creatine 0.7 1 c 0.001 PbB vs total semen count 0.03 M.05 PbB vs duration of expasure 0.47 < 0.05 PbB vs spmmatozm morphology -0.46 -<0 .005 PbB vs !sperm m~tili€y -0.46 < 0.05 Urinary cresttine vs total sperm count 0.10 M.05 Values are mean k S .D. Source: h e t o r et d. (2001) Lead Poisoning and Bone Disease Following our study of the effect of Cd on bone we then examined the effect of Pb on bone metabolism. Bone, the largest repository of Pb in the body, is not metabolically inert. Bone thus responds to environmental poisons and pollution. Occupational lead toxicity and exposure to increasingly polluted environments impair bone mineralization which may lead to increased incidence of bone disease such as osteomyelitis and osteoporosis (inflammation in the bone and ' brittle bones) in human and animal populations. This is already a big health problem in the developed countries. It is notwithstanding frequently ignored in current environmen taI UNIVERSITY OF IBADAN LIBRARY health concerns in the developing countries. We examined bone metabolism and its implications for bone disease in lead workers, We have provided evidence that a clear sonsequence of occupational lead toxicity or a polluted environment is impaired bone metabolism, specifically defective mineralization arising from decreased calcium and phosphate absorption owing to lead-induced impairment of 1,25-DHCC. This may lead to bone disease in human and animal populations, with serious implications for the livestock indusw and the economy of affected nations. This is also important in Zamfara one of the states f m w hich cattle that supply most of the beef consumed in this country comes (tables 21 and 22). The health of children may also be affected, stunted growth and rickets. Impaired bone metabolism in .occupational lead toxicity' and increased environmental pollution probably contributes to the incidence of osteoporosis already a major concern in the more industrialised economies which may also spread to developing countries with progressive industrialization. Table 21: Indices of Bone Metabolism in m d and UnexSpOSBd Subjecis Biochemical Parametem E e U n e x p d t P Total calcium (rmmM) 2.2 -t 0,02 2.31 * 0.02 2.6 <0.01 Ionized calcium ~-VI) T W a lkaline phosphahw (ALP] 32 * 1.48 33 4 1.71 0.5 > 0.05 (LUJ1) Bone isoenyme of ALP 27 * 24 k i,67 0.5 > 0.05 ~LUAl ~daplr otein 82 k 5.6 75 4 1-60 1.05 > 0.05 Albumin (g/I) 44 * 0.4 44 A 0.5 0.5 >0.05 Percent of subjects with total calcium below 2 19 4 - - Values represent the rnem k SEM UNIVERSITY OF IBADAN LIBRARY Table 22: Blood Lead, Serum Mqndum, Uric Add a d Z bc Levek in EKposed and Umxposed Sub&xb. Biochemical Parameters Expod Unexposed t C Blood lead @mM) 2.72 * 0.05 1.47 f O,M 8 9 < 0.001 mhc -MI 11z+ai1 8skz.65 4-06 < 0.001 Magnesium (nbtM) 0.90 A 0.05 0.85 k 0.06 0.66 M.05 Uric acid (mmdn) 311 A 16.6 204k 11.3 5.28 < 0.001 Values fepresent the meaa k SEM The economic and social implications of inadequate skeletal development and attendant disease have been pointed out by Scott (1995). In the eldedy, environmental pollution may exacerbate the a b m a l bone metabolism normally associated with ageing. The population of ageing subjects is also increasing in Africa and many other developing countries with improvement in economic indices (Unwin and Mkti 2000). The skeleton also provides important calcium resene during lactation (breast feeding), if this reserve is unpaired owing to environmental pollution; rickets (soft and &formed bones) may result. Rickets, a predominantly nutritional disease, has been reported to be common in developing countries (Thatceth et al. 1999; Bishop 1999). The contribution of environmental pollution to this nutritional and metabolic d i w m ay yet be unknown to the scientific and medical communities. Additionally, lead may be mobilised during normal bone homeostasis which may put the developing brain of children in developing countries at risk of lead-induced brain disorders (neurotoxic effects) such as behavioural abnormalities and reduction in intelligence quotient (I.Q.) levels elegantly enunciated by Nesdleman (1996) and Rodier (1995). Observa0,ons on the Haemopktk System in Trapid Lead Poisoning The haem biosynthetic pathway is one of the most fundamental and remarkable in the chemistry of life. It shows the greatness of nature and of God. The pathway commences with very simple p~w:ursorst;h e simplest amino acid, glycine and m intermediate of the Krebs's or citric acid cycle, UNIVERSITY OF IBADAN LIBRARY succinic acid, one of the most important systems of life, haem is born. This on addition of the protein, globin gives us haemoglobin thet pigment of life that transports oxygen throughout the body. Interestingly, this toxicant has great afhity for and unleash its deleterious and life threatening effects on this system. The haem biosynthetic pathway was one of the earliest principal targets of lead to be recognized and intensely studied, Sofoluwe et al. (1971) studied this pathway in lead workers in Lagos to infer lead poisoning. Over a century ago Garrod (1892) first identified porphyrinuria in human lead poisoning. In 1895, Stovkis demonstrated its occurrence in both clinical and experimental plumbism. Though now well recognized that lead interferes with hemoglobin synthesis at a number of steps (fig. 13) the mechanisms are incompletely elucidated. These interferences are largely responsible for the haematological toxicity of Pb. Most earlier studies have emanated from the temperate developed world with optimal nutritional status. Our report (Anetbr et al. 2002) examined the haematobiochemical effects of lead in tropical lead workers. Lead level, erythrocyte pmtopmphyrin W P ,m ), porphobilinogen, the degradative product of the haem biosynthetic pathway bilirubin, indices of Fe homeostasis; Fe, msferrin, TIBC, % Fe saturation and the haem co factor b i o m d , Cu and Zn were investigated in Pb workers. We observed that W A m etab1ism was unaltered as indicated by the absence of basophilic stippling (tabb 25), . nomall y arising from deposition of Fe in the mitochondria due to inhibition of haem synthesis. We also observed complex changes suggesting the interplay of acute phase and antioxidant responses of Cu in caeruplasmin and Cu-ZnSOD. No variation with exposure category was evident; implying absence of dose response relationship. Remarkably, elevated Zn level in Pb workers (table 23) most probably from inhalation (analogous . to supplementation) of Zn from welding fumes in the occupational envirunment was found. The activating effect of Zn' appears to have significantly restomd the activity of the major haem pathway enzyme d- aminolaevulinic acid dehy h t a s e (d-ALA), a Zn dependent UNIVERSITY OF IBADAN LIBRARY a m p~ q p h i t d -~wym itixe tm I(@. .S). Khis modulated rthe' cHeikte* :of b . Wzmimn in some I ~ t d I o g i ~ idndIic res, Eb, haematmrit @ET),m ean cell iha~mg1dbins w~~t tm-t (iMmU RC J) *war,& so observed ,(tELtj$ 259. Xhwie ~in~onsistanot h a n p appear to bomdh~a trteh e hi-k that .!a ther rmechanims may be . ~ i n d h [din B b -&sd ta. Khe .psactical application {(Elf t h ihaxe ;isi tkit Lk9 ~ x e patf (optimuml or raised Z n ! b'KPi:ol an ib ~ ~ @ l m;aBs a ntidlate af ! ledp aisankg and may 1.k @hemplanation# or idby lfmr iinstakure -workers in some . t w ~ ~ h mldphse ~e>y oui hme i d h mm y i hwe elevated blood T?b!bdldrnotihmdlinicrilw pptam. Whis :is why over the 3Pacent-f 89)m e saturation 2974-r'~1$ 9 3 1. '81 k.2.39 !0-31 .> O:Q5 TEE=' total iron binding capacity, Values are mean SEM After Anetor et.al., (2002). Table 24: Haem-precursors, Erythrocyte Protoporghm (EPP) Porphobilinogen (PBG) Haem Degradative Product, Totdl Wrlirubig in Lead Workers and ControIs Lead Worker Contds t P E m m s t e protoprphyrin * k - - (EPlp) porphobilinogen -ve -ve Total b i b i n 0.78 * 0.03 1.0 .c 0.06 3.35 c 0.00 i ~ m g l a Values are mean SEM; k = trace UNIVERSITY OF IBADAN LIBRARY Table 25: I b m b c r i t ( PCV),.RI&mgMhG A" 4 MCMC, P o i y h d a nd Ehmgm-JmM W*TS an&thdmk XRad W h e w Controls t DI %w dl) t 3.57k 0.09- 144&0! 13 4.99 4 0~00Ai MCHCWdi) 33.0 0.13 34.@&Q Mk 453: e 0; 00 1' Polpchromsia Absent Absent - - , ~ P s ~ ~ h ~ ~ s t i p p ~ i n g s M W ~ O . - . - (accumulated rRNA) Values are mean * SEM After Anelor et d,( 2002) Fig, f 3: Haem IBimyntWiiW~~ w w . P b i m o 5 m n e b y l& Pb)! After Liu! all. (=I)! c--- - - I ~ T ~ p g F % t P a % w , ~ ~ ~ in P i t r p i . * t g : ~ ~ ~ ~ h ~ r d T * ~ ~ n ~ w recognized l i i ~$ e do a aiggrmww by rat&& QE toxic mygem speszks) TlIQ. Ptl is w r S y nx~gtmmd! UNIVERSITY OF IBADAN LIBRARY currently that the global explosion in the incidence of diabetes mellitus particularly type II has reached an epidemic situation. Recent reports estimate that the total number of individuals with diabetes worldwide wiIl increase from 171 million in 2000 to 366 million by the year 2030 (Wild et al. 2004). It is even more disturbing to learn of the predicted rate of increase in real terms for the next two decades, where it is speculated that one in every four individuals will be diabetic. Not unexptedy , the. picture appears more grue-some for the developing J resource poor countries. The two widely accepted explanations for the cumnt state of affairs have been shift in dietary life style from a less calorie laden, complex carboh ydrate-based and active life style to a more calorie dense, simple sugar-based diet and a more sedentary life style permissive of obesity. The possible involvement of TOS is hardly considered. Reactive oxygen species appear to be involved in both the development and later complications of DM (Oberley 1988; Wolf 1993). Lipid peroxidation is elevated in diabetic patients. Evidence from both animal and human studies suggests that the antioxidant defence system becomes compromised prior to the development of the disease. Magnesium and zinc are important minerals which play important roles in metabolism. Knowledge and implications of the status of minerals though important is often overlooked. Understanding the roles of Mg and Zn may help in lowering the morbidity and mortality associated with diabetes. This may be particularly important in less developed (resource poor) countries like Nigeria with limited financial and health facilities. The growing awareness of the beneficial role that mineral element nutrition plays in amelioration of disease states, restoration of good health and enhanced physiological function was the key motivation of this study. We investigated 40 type-2 diabetic (ZlM, 19F) and 20 non-diabetic Nigerians as controls; examining serum Mg, Zn and total cholesterol levels. The concentrations of Mg and Zn were significantly reduced, probably suggesting depressed antioxidant status and increased demand for these nutrients in diabetes meilitus. One implication of this, is greater UNIVERSITY OF IBADAN LIBRARY susceptibility of low density lipoprotein (LDL)- cholesterol (bad cholesterol) to oxidation which is more atherogenic. The attendant risk of development of premature coronary heart disease (CHD) is enormous. Magnesium and Zn are nutritional miierals that play crucial roles in the regulation of carbohydrate and lipid metabolism as well as the antioxidant system. Zinc is a component of the potent antioxidant, Cu- ZnSOD. Zinc deficiency may also lead to deficiency of other vitamins; E, and A (Goode et al. 1991; Christian and West 1998). Thus Zn deficiency leads to reduced total bio- availability of vitamins A, E supplies and consequently total antioxidant status needed to combat the increased free radical burden in this disorder which is exacerbated by the concomitant low Mg level (Anetor et al. 2002b) (tables 26- 27). These data appear to give some credence to the antioxidant hypothesis and weaken the argument of those proponents of the antioxidant controversy. Table 26: Age Blood Glu- T o t .C holesterol, Sehm Magnesim and Zinc Levels in Diabetes M e b T. Chol. ( d l Values are mean a SEM; FBG = fasting bIoad glucose Table 27: Correlations among Blood Glucose, Total Cholesterol, Magnesium and Zinc Leveb in Dhbetic Subjects r P Ghcose vs Magnesium - 0.02 > 0.05 Glucose vs Zinc - 0.14 > 0.05 Total cholesterol vs Mg. 0,60 < 0.001 T. Cholesterol vs Zinc 0.03 > 0.05 UNIVERSITY OF IBADAN LIBRARY Increasing concerri about this well-known metabolic disease that arises from either absolute or relative insulin deficiency that may also involve receptor metabolism led us to conduct further studies. According to the World Health Organization (WHO), about 347 million individuals worldwide suffer From diabetes currently. What is more disturbing is that though this is a global disease, over 80% of those dying from diabetes come from low and middle-income countries @anaei et al. 2011; Rao et al. 2015). The majority of cases involved in the upsurge are of the type two form (n- DM). The disturbing number of increase in individuals with diabetes has created enormous problem of immense dimensions, which aside from medical aspects has huge economic challenges to governments, society and individuals. It is clear to both scientists and leaders of government that there is need for paradigm shift in the understanding and management of DM. Though traditionally, lifestyle factors, obesity etc., have been considered to be the major cause of the disease as earlier indicated, emerging reports indicate that toxicants may play a crucial role in this disorder (Edwards and Pmlialeck 2009). This is aside from the role of toxic or reactive oxygen species in the aetiology and evolution of the disease. These considerations made it instructive to us in the toxicology unit to conduct a number of studies on this increasingly exploding disease in an attempt to better understand the disease and possibly search for possible mitigating factors. One of these latter studies (Anetor et d. 2007~e) xamined the possible contribution of oxidative stress. Oxidative stress is an important component of diabetes as &firmed by our earlier studies (Anetor et al. 2002b) and its complications. Uncoupling protein 2 (UCP-2) has been implicated in the pathway inhibiting glucose stimulated insulin sectetjon (GSIS). The micronutrient, manganese (Mn) is the key component of the mitochondria antioxidant (MnSOD), and plays a critical role in the superoxide uncoupling of UCP-2 pathway in GSIS. There is a disagreement on this about p-cell function and DM.W e studied 50established type-2 diabetics and 30 non-diabetics (tables 28-30). Our results provided UNIVERSITY OF IBADAN LIBRARY evidence suggesting absence of significant oxidative stress in the mitochondria, probably excluding a role for UCP-2 - superoxide pathway in the inhibition of glucose-stimulated insulin secretion. W e called for caution in the precocious conclusion that intemption of UCP-2 activity may provide a viable strategy to improve p-cell dysfunction in type-2 diabetes. Very importantly our data suggested that the combination of increased Mn, thus increased activity of MnSOD, increased K+, reflecting potassium channel activity, partial reduction in ascorbate level, increased BMI within reference limits along with hyperglycaemia may suggest absence of superoxide -UCP-2 pathway oxidation. Our finding called for a re-examination or need to explore alternative pathophysiological pathways. Our suggested panel appears a simple approach, readily available to the average clinical laboratory, rather than the purely research-based high technology approach, involving molecular genetics (that are still' routinely beyond our reach) in current literature and promises to be of particular value to populations in resource poor countries who have to grapple with better understanding of the current epidemic that diabetes constitutes. I am glad to report Mr. Vice-Chancellor, Sir, that this paper was quite impressive to the editorial board of Biological and Trace Element Research (BTER) with an invitation to become a member of the International Association for Bioinorganic Scientists (IABS) of the United States. Table 28: Body M a s Index (BMI), Hasma Glucose, Greatinhe, K+ Lavels in Dimbetics and Non-dkbetics Diabetics Non-diabetics t P BMI ( K d d 25.27 & 0.07 23.17 * 1.65 5.78 < 0.01 UNIVERSITY OF IBADAN LIBRARY Table 2% P b m A scorbic Acid and Mampwse Levcls and Percent of both in Type2 Diabetics and Nondia- Ascorbic acid (cun0W Mn Icund(L) 3.8 * 0.007 1.8 st 0.005 Percent (k)o f Mnin DM to tbat of controls 21 1 Percent (%) of au~43rbateinDMto So - - - thatofcontrols Values are man & SEM Table 30: Correlation of Serum Mn Level with &rum Levels of Glucose, Atmrbate, K+ & C r e a W e in Dia- Cadmium and Diabetes The next in the series of our studies on this disease of growing concern was to examine the possible contribution of cadmium a ubiquitous and rising environmental pollutant (Anetor 2012) which in addition to other harmful effects has emerged as a major concern not only in environmental toxicology but also in metabolic diseases such as diabetes mellitus and its complications. Conflicting data aside, very few studies have examined a clinical population undergoing management as well as the possible modulation by a prominent metabolic antagonist of Cd, zinc. We examined the relationship between cadmium levels, glycaemic control and renal pathology (kidney disease) in established type I1 - diabetic patients in a population exposed to modern environmental health hazards (MEHHs) classified using gl ycated haemoglobin (HbA lc) to good gl ycaemic control, fair control and poor control. UNIVERSITY OF IBADAN LIBRARY Contrary to our expectation Cd level was lower in diaktics than in non-diabetics (Anetor et d. 2016) (table 3 1). One of the key messages from this study is that the protective or ameliorative nutrient, zinc demonstrated significant inverse mrrelation with Cd (table 32). The lower Cd level found in diabetics compared to non-diabetics probably reflects the modulating effect of Zn in the treated diabetics (a Zn wasting disease) given nutritional education in addition to their regular regime, including consumption of good sources of Zn. This=mayb e corroborated by the cadmium: zinc ratio which was significantly lower in diabetics than in non-diabetics, suggesting that Zn may have a profound modulating effect on cadmium poisoning or toxicity. It has been consistently demonstrated in our studies and reports From other laboratories that toxic metals mimic essential metals and consequently gain access to and disrupt key cellular functions [Shenkin 2006). This study appears to have elegantly upheld this seminal observation. It is an important concept that could be explored to ameliorate modem environmental health hazard (or poisoning) as illustrated between Cd and Zn in this report. The observed renal insufficiency with increasing Cd level may suggest that the progression of renal impairment may not be responsive to the putative modulating effect of zn. Table 31: k i n gP lasma Glucose, Cadmium, Zinc and Cd/ZII Ratio in Dibe th and Non-diabetics (Controls) FPG (@dl) 150.90 rt 79.39 96.62 11 .957 4.474 O.oOo* a (Wm) 0.05k 0.02 0.095 k 0.031 5.763 0.000* ( P d ~ l ) 102.51~10.11 98.1k10.76 1.496 0.144 tWihreh 0.002+0.000 0.004 k 0.001 5.485 0.000* SSignificant rrt the level indicated FPG; fasting plasma glucose UNIVERSITY OF IBADAN LIBRARY Table 32: Correlation of Cadmium with Biochemical In* Parameters r- value p- value FPG (mgldl) -0,196 0.133 HbAlc I%) -007 0.967 zm (@dl) - 0.317 0.014* Creatinime (mgld1) 0.149 0.258 Urinary albumin-creatinine ratio -0.172 0,196 eGFR (dmin/l.73m2) - 0-127 0.333 Significant at the level indicated HbA lc = glycated haemuglobin; eGFR = estimated glomeruiar fittration rate. Carbon tetrachloride (CC4) Poisoning Carbon tetrachloride is a simple molecule and a common domestic and industrial chemical that is profound1 y toxic to the liver. It was previously used extensively in dry cleaning and even as an anaesthetic. It is primarily hepatotoxic (damaging to the liver) where it causes two types of pathological effect. It causes centrilobular hepatic necrosis and fatty liver when administered to different types of species. An important feature of this solvent is that it is very lipid-soluble, thus well distributed throughout the body. Its target toxicity in the liver is because the toxicity of CC4 is dependent on metabolic activation of CY2El; the liver is thus a target as it contains the greatest concentration of CYP450.b is selective for isoezyme CYP2El in the rat while CYPl A1 is unaffected. It elicits its toxic effect by oxidative mechanisms, forming hydroxynonenal (HNE), a reactive aldehyde that may lead to cy tosolic calcium build up. Though extensively used, possible protective mechanisms have on 1y received measured attention. We investigated the of veronal amygdalina on Cell toxicity (Babalola, Anetor and Adeniyi 2001) and found it to be extremely protective against CC4-induced liver damage (hepatotoxicity). The advantage of this observation is that this extract is obtained fmm a common vegetable found all over the country and can be used as an antidote or prophylaxis to this chemical or related ones in domestic and industrial environment at a very cost effective rate. UNIVERSITY OF IBADAN LIBRARY Mechanistic Search for Remedy or Antidote of Poisoning An antidote is a substance which specifically blocks or reduces the action of a toxin or toxicant in general. Nearly all the investigations in the field of metabolism of poisonous compounds called xenobiotic biotransfomation arose from the studies of a scientist from Wales, Richard Tecwyn Williams. His early studies on the ring structure of glucuronic acid isolated from the urine of dogs fed borne01 which enabled him to crystalize the conjugate that he employed as a base substance for the elucidation of its pyranoid structure. This encouraging outcome stimulated his interest in the biotransformation of exogenous substances, which led to a series of reports on the fate of phenols (major bi-product of the environmental toxicant, benzene), terpenes, and sulphonamides. The concept of what is today called antidote is traceable to James Gillete, a major figure in biotransformation who along with Bert Ladu, Jr at the Laboratory of Chemical Phmacology/Heart and Lung Institute at the National institute of Health (NM) where B.B. Brodie was the head (Lane 2014). Gillette's studies on cytochrome p450 were very significant and he succeeded Brodie in that Laboratory. Another remarkable pair of scientists, indeed a couple, James and Elizabeth Miller, made seminal contributions to the field of biotransformation (Xenobiotic Metabolism). They were initially interested in understanding the conversion of synthetic and naturally occurring chemicals to toxic or chinogenic electrophilic metabolites and the regulation of xenobiotic metabolism. The origin of their studies can be traced back to the late 1940s when the Millers demonstrated that a foreign chemical could be biotransformed to intermediates that covalently bind to macromolecules such as IMA (adducts). The administration of hepatocarcinogenic aminoazo dyes (cancer causing dyes) to rats culminated in the covalent binding of metabolites to protein in the liver. Interestingly, very little binding was observed in non-target tissues which did not exhibit tumor formation UNIVERSITY OF IBADAN LIBRARY (tumourigenesi s). These in vestigatom elegantly demonstrated that factom which influenced in vivo binding of aminoazo dyes to protein also influenced hepatocarcinogenici t y (cancer development in the liver), an observation which led to their suggestion that covalent binding of metabolites to liver macromolecules was an essent i a1 step in carcinogenicity. Laying the foundation for possible intervention by exploiting this pathway. They extended this line of thought to carcinogenic pol yc yclic aromatic hydrocarbons (PAHs) when they observed that metabolites covalently bound only to protein in the skin (Lane 2014). James Miller demonstrated the oxidation of a foreign compound in a cell- fm system by enzymes later identified as cytochrome P450. He demon- strated that liver microsomes reduced the azo bond of 4- dimethylaminoazobenzene and that NADPH (a derivative, coenzyme of nicotinic acid, vitamin B3) was required for the catalytic activity. James Miller also observed that flavin adenine dinucleutide (FAD) a derivative and coenzyme from riboflavin (vitamid33 (a micronutrient), was required for azo dye reductase activity. These results provided a mechanistic explanation for the protective effect of riboflavin on carcinogenicity of the toxicants, aminoazo dyes. This in part gave the impetus for the thrust of my research in employing endogenous modulation of toxicity as an antidote for toxic states or poisoning. These observations implied that dietary substances, largely the micronutrients embracing the vitamins can inhibit the carcinogenicity of chemicals by influencing their biotransformation. This also provided an early foundation of cancer chemoprevention, the use of natural agents to prevent, delay or reverse the process of careinogenesis. James Miller carried out several other experiments extending this principle; biotransfomation of chemicals, though they did not pursue this line of research far enough, it paved the way for the discovery of cytochrome p450. A very important contribution of the Millers for which many toxicologists and pharmacologists are very grateful is the discovery that foreign chemicals including drugs can UNIVERSITY OF IBADAN LIBRARY induce the synthesis of liver enzymes that can biotransform the compound administered including foreign (toxic) chemicals. Investigations on microsoma1 enzyme induction provided a mechanistic understanding of the inhibitory effects of some PAHs on aminoazo dye carcinogenesis. The studies by the Millers formed the basis of the investigations of Allan Conney (Lane 20141, who showed that increase in metabolism could be antagonized by inhibitors of protein synthesis. One contribution of the Millers to bio- transfmtion and the concept of antidote is the important unifying - concept that most carcinogenic and mutagenic (mutation causing) chemicals are not carcinogenic or mutagenic by themselves, but that the compbunds must undergo biotransfodon to reactive electmphilic inter- mediates that exert their toxic effects by covalently binding to critical sites on DNA or RNA, and protein (lane 2014). This observation opened up the field of mutagenesis as it relates to chemicals and development of fast mutagenicity tests of potential humao carcinogens. The induction of these enzymes is important in toxicology as it leads to an accelerated biotransfarmation of drug and environmental chemicals in vivo and so aXkm their action and toxicity or poisoning for a more favourable outcome or protection. The other aspect that influenced my line of research in this *tion is another seminal observation by Parizek and Zahor (1956); Zahor (1957) on the toxic effect of cadmium on the testes. The potent deleterious effects of Cd on testicular tissue were first observed as early as 1919 by Alsberg and Schwattz (1919). They observed that administrstion of Cd salts in animals caused "bluish dismloration of the testicles7'. Their report escaped further examination fm about forty years. Parizek (1957) reupened the subject and thoroughly investigated the destructive effects of Cd on tesEicular tissue. He observed that after the parented administration of Cd (2.2m@g), the testes became swollen, dark red, or purple. The weight fell rapidly, turning small, hard and yellowish. This sequence of events was followed by haemomhagic, edematous and ultimately necrotic appearance. Here we may recall the remarks of Timbrel1 UNIVERSITY OF IBADAN LIBRARY (2009) on toxic responses. Parizek and Zahor (1956) and Parizek (1957) observed that the effect of Cd on the testes were sterilizing and developed rapidly, making the experimental animals rapidly sterile in as short as 24 hours. Very importantly, Parizek (1957) demonstrated that large doses of zinc salts could prevent the action of Cd on the testes. Previous studies in the early and late 1960s (Kar et al. 1960, Gun et al. 1961; Mason and Young 1967) made similar observations. Zinc deficiency in animal models affects the gonads; it has been observed that Cd administration can displace significant amounts of Zn (Singhal and Merali 1979). Before then it had been suspected that Cd might exert its initial injurious effects on Zn-dependent spematogenic elements. This suggested a form of antagonistic metal- metal interaction. Zahor had suggested that Zn might be essential for n o d m etabolic activity and or tissue integrity at some testicular site(@, where Cd could displace Zn. This study reaffirmed the possibility of using the antagonistic relation- ship of an essential element to a toxic one as a basis of antidote effect, a principle in which I have much interest and faith as one of the most pragmatic approaches to unpoisoning a poisoned world as our studies bore out. Mason and Young (1967) had also confirmed that both Zn and Se (another micronutrient) are extremely effective in preventing testicular injury produced by Cd. We have consequently examined the effects of micronutrients to assess the metabolic influence of micronutrients in affording protection against the various metabolic and functional alterations caused by toxicants like Pb, Cd, As, Hg and other toxicants like benzene. It is also of interest that both Se and Zn are capable of significantly ameliorating Cd-induced met ablic disturbances. W e demonstrated this in the study in diabetes just discussed above (Anetor et al: 2016). These protective or antidotal effects largely appear to lie in the ability of these biometals to reverse the high affinity of Cd for sulphydryl (- SH) groups. It is postulated (Gunn et at. 1966) that the micronutrient Se complexes with Cd preventing sufficient free cadmium from reacting with bioavailable SH groups. UNIVERSITY OF IBADAN LIBRARY Descriptions of some of these studies follow. b a dP obning and Brain Function: A Biochemid Panel for Silent Lead Neurotoxicity Neurotoxicity from lead exposure is of great concern, especially as lead is ubiquitous in the environment and even at low concentrations can elicit neurological damage; ideal blood lead level is zero. kve l s as low as 2Clgldl have been associated with reduced IQ and behavioural deficits (Lanphear et al. 2005; Gilbert and Weiss 2006). Emerging reports suggest that deleterious effects of toxicants may not be clinically manifest for a long time after exposure to toxicants like Pb. This period is referred as the period of silent or latent neurotoxicity (Fretham et al. 2014). It is characterized by persistent biochemical or morphological injury which remains clinically unapparent unless explored by investigations. This situation may be comparable to the process of carcinogenesis in which molecular and cellular damage are evident long before the manifestation of cancer. Mechanisms of lead toxicity are incomplete1y understood and only few studies have examined these with the multiplicity of contending factors in the developing countries and their implications. We examined metabolic status and common health problems in occupational lead exposure in eighty-six lead workers fifty-one unexposed participants; 137 participants on the whole. Blood Pb level and serum K+ were significantly higher in Pb workers than in controls. It should be noted that K', like glycine has a potent effect on transmission of nerve impulses and neuron firing. In contrast total and ionised calcium, chol inesterase (Ch E) and urinary ascorbic acid levels (nervous system is rich in ascorbate and very beneficial to it's Function) were significantly lower. Calcium and ChE ppeared in the multiple regression and principal component analyses model, indicating important relationship to PbB level (Anetor, Adeniyi Taylor 2002d) (tables 33 and 34). We suggest that these lead-i nduced biochemical changes have hpnant neurological implications such as imtability, UNIVERSITY OF IBADAN LIBRARY insomnia and headache not commonly appreciated. Evaluation of these biochemical changes in combination with blood lead level (PbB) may constitute a panel of biomarker of silent neurotoxicity (braindamage). It may also serve in children as an early marker of functional deficits apparent later in life, congruent with Barker's hypothesis of fetal origin of adult disease. Another important inference from this study is that optimum levels of the nutrients, calcium, ascorbate and K may be protective of neurotoxicity and compromised levels permissive of the disorder. Indeed most of the neurotoxic effects of lead are exerted by interfering with calcium level. Table 33: Common Health Problems or Complaints of Lead Workers Health Problem/Complaints Duration (weeks) Percent ( 95) Headache and pains 43 50 Easily tiredlg&eral malaise 14 16 Non-specific 12 14 Abdominal symptoms (Colic) 7 8.1 InsomniaBleep disturbance 5 5. 8 IrritabilityLos of memory 5 5.8 No symptoms (Nil) 5 5.8 Impotencdhfertility 3 3.5 Drowsiness 3 3.5 Total with neurological symptoms 7 1 83 Mainly symptoms and complaints that are neuro1ogically related Table 34: Blood Lead Levels and Biochemical Constituents Important in Neurological Function in Lead Workers and Control . Lead wwkm Controls t-v* p-value C= 86) (n= 51) Blood lead(umol/l) 27.72 & 0.05 1.47 i0 ,07 18.91 c 0.001 K+ 4.7 * 0.10 4.2 rt 0.13 2.63 . < 0.01 T. Ca (mmdi) 2.22 2 0.09 2.30 rt 0.08 2.6 c0. 01 I -W-) 0.88 * 0.03 0.99 * 0.04 6.67 < 0.001 SerumChE QUA) 2582 * 98.83 3 126 i 82.05 3.07 c 0.005 Urinary a s e d c a cid (msllO0 msl 9.0 * 1.62 14.3 + 1.23 1.57 < 0.02 emtinine) b Values are mean * SEM UNIVERSITY OF IBADAN LIBRARY Lead Poisoning and Neural Qrain) Nutrients Lead as we have seen above is a prime toxicant, but is particularly important as a newtoxicant; it is one of the most widely used chemicals both domestically and in industry. The mechanism of the neurotoxic effects of lead are poorly understood (Arena 1979). In recent years there have been numerous indications that more investigations on the mechanism or mode of action of lead are needed (Walker 2000). Magnesium and thiamine (vitamin Bl) play important roles in the adequate functioning of the nervous system. Magnesium deficient y among others is associated * with central nemous system symptoms including anorexia, pe~sorialityc hanges, weakness, tiredness, vertigo, confusion, n e w m e s s , initability, tremors, involuntary eye movement, anxiety, insomnia, and the chronic fatigue syndrome (Soldatovic et al. 1998). These are also some of the protean symptoms associated with Pb toxicity (Sepallainen et al. 1983). Interestingly, these e- two nutrients play very pivotal roles ln energy metabolism. Thiamine (fig. 14), as part of TPP is needed for the generation of acetyl-coA to enter the Krebs's cycle for greater energy yield and Mg as the cofactictor needed for ATP activity and as a cofactor for hexokinase. Though the subtle effects of Pb on the developing CNS is well dmumented, those on the adult CNS are not as well known. This is probably more so in environments with high c~bokydratei ntxke* where magnesium, thiamine and other micronutrients, needed for adequate metabolism and neural healthmay-be required in increased amounts. This study on n-1 nutrients and lead poisoning was designed to shed Light on this aspect of the subject (i.e. interaction bt~een.Pban d neural nutrients) and contribute to improved url-bing and p s i b i y as a basis for an antidote for the neumt&xicaeffects of Pb. UNIVERSITY OF IBADAN LIBRARY fig. 14: Structure of thiamine [B The subjects were classified according to exposure category as in our previous studies. The blood lead level was higher in Pb workers but not significantly different (P > 0.05). In contrast magnesium and thiamine levels were significantly decreased (P0.05; P4.01) (table 35) respectively. The calcium level was also lower in Pb workers, than in controls bGt was not significant (P > 0.05). Additionally, thiamine was significantly inversely correlated with BPb level (r-0.50;P < 0.0 1). Magnesium level was simi larl y negatively correlated with BPb but was not significantly (r-23, PS.05). Calcium was in addition significantly inversely correlated with BPb level (r - 0.41; P < 0.01) (table 36). Remarkably, the low exposure category with the lowest thiamine level ( ~ 4 . 0 5 ) compared to controls and significantly reduced Mg level ( ~ 4 . 0 5 )s howed the highest BPb level, which was significantly higher than in controts (p4.05) unlike when the whole cohort of lead workers was compared with controls (table 37). Blood lead level in the controls though about half those in earlier reports, is still higher than cumntly acceptable levels in less polluted environments and may also be harmful ;n the face of reduced thiamine and magnesium levels. These i esults demonstrate that relatively low BPb levels, can enhance the absorption and potentiate neurotoxicity in the presence of decreased thiamine and Mg levels, particularly in calorie overdependence; thus modulating dose - response relation- ship. UNIVERSITY OF IBADAN LIBRARY Table 35: Age and Blood/Serum Levels of Measured Parsmeters in aU Lead Workers and Controls Lead workers Contrais (n = 47) (n =25) t P Age (Yearn) 33.0 + 1.2 36.0+ 0.50 2.3 < 0.05 Lead (umoyL) 0.865 0.06 0.754 & 0.073 1.2 > 0.05 Thiamine (-a Calcium (rnmolk) 2.27 + 0.I 2.42 + 0.1 - 1.14 > 0.05 Table 36= Cornparisan of Lead, Thiamine. Magnesium and Calcium ]Levels between Severe Ex- (group 1) snd Controk Group 1 Controls (n = t P 23) (n =25) M (um01IL) 0.820 & 0.170 0.754 & 0.073 0.40 > 0.05 Thiamine (nmd/L 40.68 + 6.64 58.23 5.46 2.6 < 0.05 Magmsium 1 c- 1.0 k0.I 1.1 ~ 0 . 0 5 0.1 > 0.05 Calcium (mmdllt) 2.25 + 0.25 2.42 + 0.1 0.4 > 0.05 Table 37: Comparison of Led, T h b d m , M a p d u r n and Calcium Lev& between Gmnp Three (bw qmure ca-ry) and Controls Gnwp 3 Controls (a = 10) (n =25) t P (luaom) 0.995 2 0.0 13 0.754 & 0,073 2-5 < 0.05 -I- 37.44 + 4.42 58.23 + 5.46 2.3 < 0.05 Magnesium(mmol/L) l.Ok0.01 1.1 k0.05 2.5 < 0.05 Calcium (mmdL) 2.28 + 0.13 2.43 + 0.1 1.0 >0.05 Table 38: Correlation among M,Th iamine, Magpsimi d C d c h iL evels in Lead Workem Lead m tblPraiae - 0.50 < O*Ol h ~ l ~ ~ l ~ ~ g d ~ r- 0n23 > 0.05 hiad vs &urn - 0.41 < 0.01 T b i s d o e v s ~ u m 0.20 > 0.05 Wdne vs calciom 0.20 > 0.05 Magnesium vs calcium 0.07 > 0.05 UNIVERSITY OF IBADAN LIBRARY The non-significant1y increased blood lead level in lead workers compared to control, could probably be due to the short duration of exposure; about 1-5 years compared to those studied by Adeniyi and Anetor (1999) who were exposed for over thirty years. Despite this, there was an associated significant reduction in the levels of thiamine and magnesium (p c 0.00, PC 0.05) respectively in lead workers compared to controls. This suggests that lead has an antagonistic effect on these nutrients. This may be consis tent with the observation of Shakman. (1974) and Mahaffey and Vanderveen (1979) that acceptable Pb levels in the presence of reduced neural nutrients may be neurotoxic. The exact mechanisms for this phenomenon have not been completely el ucihted: competitive inhibition by toxic elements may be operant. This suggests increased demand for magnesium and thiamine in lead exposure. Magnesium is important for the activation of thiamine to its metabolically functional moiety and involved in its metabolism. Indeed, in the presence of magnesium deficiency, thiamine deficiency cannot be wmted, as it enhances thiamine deficiency (Zieve 1969). The significantly decreased thiamine level suggests antagonistic relationship between lead and thiamine. The exact mechanism maybe multifaceted. The side chain hydmxyl group and sulphur in the thiazole nucleus may be chelated by lead (See fig. 14) probably as part of the general affinity of lead and other heavy metals fw sulfiydryl GSH) groups. Thus, more of the vitamin may be required to counter the toxic effects of lead, leading to increased demand in lead toxicity. Thiamine administration has been found to reduce the toxic manifestations of lead (Bratton and Zmudzki 1981; Flora and Tandon 1986). The side chain hydroxyl group and sulphur atom at the thiazole nucleus of thiamine participate in chelation of lead (Flora and Tandon 1986). Tandon et al. (200 1) have recently observed that the daily intalce of vitamin B l along with vitamin C may prevent the accumulation of lead and reduce its toxic effects particulariy in those regularly exposed to lead). Thus, it is most probable .t hat lead in taxication causes magnesium deficiency, which in turn interferes with responsiveness to thiamin6 by probably hindering the UNIVERSITY OF IBADAN LIBRARY fornation of thiamine pyrophosphate, which in addition to its many metabolic roles, is involved in the synthesis of a component of the neurotransmitter, a ~ eyt lc hol ine (B erdani er 1998). Very importantly, lead and thiamine levels were significantly inversely correlated (r -0.5, p < 0.01). An important implication of this observation for our envimment (or the developing countries) where there is a dis- proportionate consumption of carbohydrate, requiring inertwed thiamine and magnesiym for appropriate meta- bolism md utilization, is that the inc& demand for thiamine implies a need to have a higher recommended daily intake (RDI) or prudent dietary intake (PDI) for this nutrient; ta either eliminate or ameliorate the neurotoxic effects of lead exposed population. This is an important public health message for Mars and environ. A striking and important okwation in this study is that the lowest exposure category (lowest lead dose, with the least thiamine level) demonstrated higher lead level and was dlgtlificantly higher than in controls (PC 0.05) (table 36). Thus reduced thiamine level has a potentiating effect on the @sorption and toxicity of lead especially in the presence of significantly decreased Mg level. Thus, though lead level may be mlatively low in a given population, its toxicity, including neurotoxicity can be magnified by relative unavailability of thiamine. Again bringing me to call for a revision of Paracelsus' dictum; 'the dose alone solely determines the poison'. The findings reported in this study (Anetor et al. 2007~) have largely contributed to the understanding of the subjeCt of lead nmtoxicity. They show that dose-response relationship may not be the major determinant of the absorption and possibly toxicity of lead, particular1 y its neurotoxici ty (table 37). This implies that even relatively low lead Levels may be potentiated by decreased thiamine and magnesium levels, particularly in predominantly carbohydrate dependent ~giunsw, here them is an increased demand for thiamine and gagnesim required for p p e r metabolism. The observation here appears consistent with the recent views calling for a rethink of risk assessment by toxicologists (Colacci and Kleinstreuer 20 15). UNIVERSITY OF IBADAN LIBRARY Industrid Pollution: Contribution of the Cement Industry Many substances contribute to environmental pollution. One that is very pervasive and overlooked is the contribution of cement. The cement and steel industries are key to industrialization in any country. Activities related to cement production and utilization are numerous in many developing countries including Nigeria; Dangote group is welcomingly expanding this sector. This has also givm rise to an upsurge in the number of factories and paces of production. Following conflicting reports on the composition of cement and possible toxic constituents, we set out to investigate the composition of cement in Nigeria and United States of America, through collaboration with the University of Texas Medical Branch, Houston, United States of America. Introduction of toxic metals into cement has been related to combustion processes (Bhatty 1995). Owing to sustainability of cement production, many manufacturers have had recourse to alternative sources of energy and secondary fuels derived from industrial by-products that may be toxic (Bhatty 1995; Yan et al. 2010). Examples of such a1 ternative source of fuels include solvents, used tyres, waste oils, paint residues, biomass such as woodchips and sewage sludge (Bhatty 1995). These varied fuel sources are the probable contributors to the elevated toxic metal levels released from factories reported by different investigators. Elevated concentrations of toxic metals may result in the following: Induction of oxidative stress via production of reactive oxygen species or reduction of antioxidant defences Disruption of calcium homeostasis Induction DNA damage z - Interaction with sulph ydryl (-SH)gr oups Disturbances of haem biosynthetic pathway Presence of some known carcinogens (Templeton and Liu 2010) UNIVERSITY OF IBADAN LIBRARY Some leading investigators, such as Satoh et al. (1994) have reported that chromium induced nasal carcinoma in workers exposed to chromium: the workers were diagnosed of carcinoma of the nasal region after exposure duration of an average of about 8 years. Zhang et al. (2011) in their study reported increased DNA damage in workers exposed to Cr (VI). The findings of these investigators suggest that the health impacts of metals are more of chronic episodes than acute. The highlights of our findings in the Nigerian- United States studies (Ogunbi leje, Sadagoparamanuja m, Anetor et a1 . (20 13) conducted using graphite furnace atomic absorption spectrophotometry (GF-A AS) revealed that total Cu, Ni, Cr, Cr (VI) and Mn were significantly higher in USA cement dust. Nigerian cement dust in contrast and disturbingly contained higher concentrations of the key toxic metals, Cd, Pb and Hg. Some several fold than those in the USA samples (table 39 & fig. 15). It is also remarkable that some of the metals found in these dusts are established chemical carcinogens. Table 39= Statistid Spmmary of Mtasmd Heavy Metak and Cr (VI) Comcemtmtiom m Cement Ikrst from USA 0a nd Nigeria (N) d Clinker from N i(C ) Fe (~lbg-1) 23$87.7+1268.2 17,SS6.5~IlIS.S 21,133.7+809.6 SOUKC: Qynbileje. S ~ a m a n u j a mand Anetor et al, (201 3) UNIVERSITY OF IBADAN LIBRARY Data from the study on cement dust support the hypothesis that cement dust contains several toxic metals and Cr (VI) which can increase the risk of metal related diseases, thus acting as an independent risk factor in all those exposed to cement dust. Consequently, it is recommended that long-term consequences of human exposure to cement dust should be UNIVERSITY OF IBADAN LIBRARY investigated relative to the elements reported in this study. Many studies are in progress in this regard. These data suggest need for additional human studies relating the toxicity of metals and health effects in cement factory workers. Cement factories in Nigeria appear to be major contributors to environmental toxic metal contamination. With the rapid industrialization of Nigeria, it will be imperative that laws should be enacted in order to protect both workers in the industry and residents of the immediate envirofiment. As a prophylactic measure, some of the principles we have enunciated in our studies could be employed. Modulatory Effect of Zinc on Host Defence (Xmmune Fuoction) in Welders and Cement Block Moulders As fallow up from the above study, we under took to evaluate the modulatory effect of zinc on a major host defence system of the human body, the humoral immune system. In an attempt to raise the standard of living and improve their economies, developing countries are emphasizing both small and medium scale enterprises (SMEs) on the understanding that SMEs play a substantial role in employment generation and national development (Akingbunola 201 1). Welding and cement block moulding are among the most prevalent of these small scale industrial activities but associated with excessive occupational exposure to toxic substances such as Pb, Cd and many others which occur due to lack of proper workplace control measures. The upsurge observed in welding and cement block moulding activities in these countries may be related in part to the relatively low level of education required in these occupational activities. A country like Nigeria is a good case in point to assess the potential human health effects posed by these two occupations where there may be exposure to toxic metals with one also associated with high degree of exposure to an essential metal such as is seen in welding where there is simultaneous exposure to both toxic metals and the essential metal, zinc whichbas substantial effect on immune function. UNIVERSITY OF IBADAN LIBRARY Our study was conducted as outlined below. Thirty welders, thirty CBMs, thirty unexposed partici-pants were studied. Cadmium, Pb and Zn were determined using atomic absorption spectrophotometry. Key components of the humoral defence system; immunoglobulins, IgA, IgG and IgM were evaluated using ELISA. Total lymphocyte count (TLC) and monocyte (TMC) were also determined using standard haematological methods. Lead and Cd were expectedly significhntly higher in welders and CBMs than in controls. Cadmium was significantly higher in welders than in CBMs unlike Pb. Remarkably; Zn was significantly hj gher in welders than in CBMs. Interestingly the anti-bodies IgG and IgM in welders were significantly higher than in CBMs; IgG being approximately two fold in welders (table 40). Monocytes were significantly higher in CBMs than in welders. These data suggest antagonism of Pb and Cd to Zn by the lower levels of zinc in the exposed groups and the humoral immunomodulatory effect of zinc, by the higher levels of immunoglobulins in welders with higher zinc levels (Adeniyi et al. 2016). UNIVERSITY OF IBADAN LIBRARY Table 40: Lead, Cadmium, Zinc Leveb and Immuaological Paramtern in the Study PopulaLlon and ControI Welders CBMs Control Parameters Mean *SD,M ean Mean+ SD, Mermt SD, P-value Rank Mqaa Rank Mean Rank ' s Monayte (10 Ifi!) 0.2 d.1, 25.1 0.5 & 0.2, 64.5 0.3 * 0.2, 47.0 0.00 I Lymphocyte (10 lgrl) 2.W.6 2 . e 0.8 2.2 A 0.5 0.003 PC 0.003; 0.002 & 0.001 statistically significant CBMs =Cement block moulders Source: Adeniyi et al. (2016 ) UNIVERSITY OF IBADAN LIBRARY The data from'this study suggest that exposure to welding hkes and ceimnt dust perturbed humoral immune system 'aUn ' d is inodirlated by the higher Zn level in the welders. The higher Zn level in tbe welders and the correspondingly higher pphocyte and immun~glo6dinl evels in the same group .appear argue strongly for a modulatory role for Zn in response in these workers. This appears supported by the ' findings in the CBMs "with low Zn levels exhibiting 8@.. ificantly &ceased Igo compared to the welders: One 2 7 lmpricati oh of these data is that the immunosuppressi ve roles ~f toxic metals swh as Pb and cadmium abundant in our environment may be modulated. by raised zinc level. An indirect 'support for this 'appears to be demonstrated by the &tagonisin of Pb and Cd to Zn by the lower levels of zinc in the exposed p u p s than in controls an tnd associated indices of respanse and may explain why here could be varied susceptibility 16 illnesi Sn occupationdl y exposed individuals. The data imply that cement block workers may benefit from zinc supplementation. This study appears to corroborate our previws study (Anetor and Adeniyi 1998) and adds to the mitigating or antidotal role of zinc in many pathologic states. (& sease condittms) iron Poisoning in Pregnancy Iron (Pe) remains a commonly prescribed supplement in pregnancy owing to the widely held belief that the requirement of Fe during gestation is very high and may be difficult to fulfill particularly in those entry pregnancy with low Fe level. While this may be true in a few instances, the majority of women do not require most of the iron supplements they consume (Whittaker et al. 1991). Ortega et al, (1998) have also contenW the usefulness of iron supplementation in pregnancy. Consequently, it has been suggested that Fe status be monitored during pregnancy and Fe given when indicated in addition to improving the consump!ion of good sources of iron (Ortega 1998). UNIVERSITY OF IBADAN LIBR RY While this convoversy is ragng, reports indicate that iron is a free radical generator (pro-oxidant ) and that supplements may put an individual at risk of excessive iron intake or poisoning (Halliwell and Gutteridge, 1998). Indeed the chemical properties of Fe render it a potential hazard within the organism in that ferrous ion ( ~ e ~ 'i'n small non protein shiejded chelates can catalyze the production of oxygen radicals or reactive oxygen species, which in turn can lead to peroxidation and radical chain reaction withg molecular damage. Iron is involved in the Fenton reaction, generating hydroxyl radical (OH-) which is particularly toxic. Indeed it is one of the most reactive forms of the free radicals, Thus iron is important in toxic celluim injury (pietmngelo 1998). The viciously reactive O H once generated attacks hatever it comes in contact with (Pietrangelo 1998). If the hydruxyl radical i s generated adjacent to DNA, it attacks both the deoxyribose sugar and the purine and pyrimidine bases forming multiple products. Less than a decade ago, Lachili et al. (2001) reported that iron overload could promote the generation of free radicals and these can result in deleterious cellular damage. Additional 1y these investigators observed that a-tocopherol level was lowered in individuals with iron averlaad. This suggests a state of oxidative stress. Albumin, urate, vitamins E and C are chain breaking antioxidants within membranes and lipoproteins, these could be easily employed in evaluating antioxidant status in pregnancy. It is important to recall that there is no regulated exation of Fe in Fe overload. Thus iron overload may exist in pregnant subjects who take iron supplements, and this might cause oxidative stress in them with attendant pathotogies. Iron supple- mentation in pregnancy is currently a routine practice in most pregnancy care centers (ante natal clinics) particuiarly in developing countries. Tndismiminate im administration may carry gwer risks than hitherto recognized. This possibility and the hemagnitude of the eomqwences have not been adequately explored or ~ e i v e dth e level of attention it UNIVERSITY OF IBADAN LIBRARY deserves. This study was therefm conducted to examine the possible risk non discretional iron supplementation may constitute in pregnant women with particular attention to oxidative smss and its public health significance. The pregnant women were divided into two groups pregnant women on Fe supplement, non-supplement pregnant women from non-drug using Christian sect. They were further classified into the three trimesters of pregnancy. Our findings suggest comiderable depression of antioxidant status in pregnant women on Fe supplement (tables 41-45) Anetor et al. (2009). Table 41: Age, -timi, Anthmpometxk hdhs, Iron, Ascorbate, Copper, a-tompheml, Bilirubin, Zinc Lmek and Fruit and Vegetable Consumption in Supplement 4 Non-mpplement Groups Values are mean 2 SD Soume: Anetor et d. (2009) UNIVERSITY OF IBADAN LIBRARY Table 42;, ~ t b m p o m t r lIcn dices, Serum Iron and Antioxidant Levels in the Three Trimters of -- Pregnancy In the Supplement Group -- I Per cent (9%) I 1 1 I ; ? I I F M T rimester . Second Trimester Third Trimester Changes (between , - dl,I a "i - - (n=10) a"- . - (n=23) In=25) , l*&3d % C - - - t C . +- - Trimesters) Age (Years) 28.40 rt 4.53 26.00 k 4.25 26.81 A 3.94, , ' > , . I t G-tion (Months) 2.10 * 0.74 5.43 + 0.73 8.08 * 0.74 >? ' Height (m) I 1.59 & 0.26 1.59 * 0.29 137 & 0.23 Weight ht(Kg2 68.10 s 6.02 65.57 ? 10.14 66.28 2 13.2 -2.67 BMI ( W m 26.78 rt 5.45 26.07 * 10.14 27.524 1.51 2.76 Iron (IrmaVIl 10.69 k 4.15 21.30 6.80 23.16 * 10.14 1 16.65 Axorbate (mmoV1) . . , J9.7 1 * 4.39 16.82 k 5.91 14,98 d.23 -23.5 BiNrubk (pmM) 2.14 * 0.83 0.70 1 0.57 a60 & 0.38 -47.36 C0pp.r ( c L ~ ) 15.00 & 6.I 2 15.93 k 6.26 16.08 A 10.93 7.2 Vitamin E (mmoVt) 11. % k 3.35 10.85 * 4.24 -0 2 2.56 -17.22 Uric acid (imoV1) 21 1 -00* 80.36 155.42 * 84.12 135.59 * 42.8 -36.02 Zixlc (pm0V1) 17.68 k4.69 15.49 * 5.23 14.40 14.09 -8.55 Values are mean SD; Negative sign (-) before figures indicate decreases UNIVERSITY OF IBADAN LIBRARY Table 43: Anthropometrlc Indices, Serum Iron and Andoxidant Levets in the Three Trfmesterrs of Pregnancy in Non-supplement Pregnant Subjects (Controls) Per cent (9%) First Trimester Second Trimester Third Trimester C h a w (1142) (n=W In=W) (betw&a l*& 3& Trimesters) Age (Years) 25.5 & 4.53 29.20 * 4.08 25.57 * 4.88 - ~ k t i o n(M. onths) Height (Meters) Weight (q BMI (Kdm) Fe ImmoM) Ascorbate ImmoM) Bilirubin {pmom) Cu @moI/l) Vitamin E ImmoVI) Uric acid (IrmoM) Zn (IsrnoVI] VaIues are * SD; Negative sign (-) before figures indicate decr;eases UNIVERSITY OF IBADAN LIBRARY Table 44: Antbropometrfc Indices, Serum Iron a d A ntioxidant Levels In the Three TrSmesters of Pregnancy tn Subjects on lron Supplements 1" Trimester 2' Tri-r 3m Trimester F-value -P (-10) (a431 (a=25) Ape Wears) 28.40 * 4.53 26.00 * 4.25 26.81 k 3.94 4.16 0,073 G-&tion(Months) Height (Meters) Weight (9 BMI I W m 1 Iron (IrmoVL) Ascorbic e e i d ( m d ) Bilirubii(ymoVlL) Copper (pmoVL) Vit, E ImmoYL) Uric acid @mom) zinc (CrmoVL,) UNIVERSITY OF IBADAN LIBRARY Table 45: Correlation of Iron with Antioxidant Levels in Supplement Pregnant Women r-values p-values Ascorbic acid (mmoY1) -0.299 4-05 Bilirubin (pmoY1) -0.278 4.05 CU (Clm~w) -0.43 1 4.01 Vitamin E (mmoV1) -0.120 9 . 0 5 Uric acid (CrmY1) -0.383 4 . 0 5 . Zn @moVI) -0.369 4 . 0 5 Taken together these data add and extend the growing mass of knowledge suggesting iron supplementation is associated with profound oxidative stress with associated pathologic and clinical correlates which may present as teratogenic effects (birth defects), habitual abortions, retarded intrauterine growth, and low birth weight infants, pre-eclampsia and other complications of pregnancy. Thus, there is the need to exercise caution and discretion in the use of Fe supplements in pregnancy with each case considered on its own merit and more importantly calling for the need to evaluate antioxidant status in pregnant women, including determination of Fe , level, before and during Fe supplementation when indicated. Owing to the seemingly preferential demand for ascorbic acid in the Fe supplement subjects, efforts should be made to improve the supply of ascorbic acid to combat the intense oxidative stress in these pregnant women which may assist in ameliorating the high maternal and child morbidity and mortality rates which may be unwittingly exacerbated by Fe supplementation culminating in iron poisoning. The data also suggest that an up-regulated supply of antioxidants, particularly vitamin C and Zn may have synergistic antidotal effect in pregnancy. Oxidative Stress in Pregnancy Pregnancy is an important state in the life of living organisms, as without this stage there will be no offspring and 'thus extinction and end of existence. It is associated with a series of small continuous physiologic adjustments that affect metabolism of all nutrients (King 2000) due to raised metabolic rate (hypermetabolic state) in the pregnant state. UNIVERSITY OF IBADAN LIBRARY Attendant oxidative damage (the imbalance between the rate of generation of free radicals and bioavailability of their antidotes, antioxidants) is an inevitable side effect of cellular metabolism leading to genome instability and associated pathological correlates (Thornson and Orvig 2003)'. Oxidative stress arising h.om hypemetabolic state in pregnancy, the concomitant change in nutrient metabolism and their possible contribution to the distressing foetal and maternal morbidity and mortality have only received limited attention particularly in a region of the world where malnutrition is also of serious concern. Forty pregnant women divided into the three trimesters of piegnancy and 25 non-pregnant individuals of similar demographic and anthropometric characteristics were studied; specifically examining the levels of Cu, Mn, and Zn. The level of uric acid, an end product of nucleoprotein metabolism, and an important endogenous antioxidant was also examined. We observed significant reductions in the levels of Mn and Zn in the pregnant state. Unlike the latter, Cu was increased progressively while the endogenous antioxidant urate was significantly reduced in the pregnant state (Anetor Adelaja and Adekunle 2003) (table 46). Remarkably, Zn levels declined steadily in all 3 trimesters, but only significantly in the last trimester, while Mn and uric acid were significantly more elevated in the third trimester than in the first. Our study revealed that the changes in the antioxidant status are attributable to the second and third trimesters. Table 46: Serum Levels of Micronutrients (Cu,M n, Zn) and Uric Acid in Pmgmant and Non-pregnant Women Non- p-t subjects P-t t - value P -value @=w S(unb- =25) cu( ~ d d l ) 204 -7* 5.3 137.4 * 5.8 8.3 < 0.001 Uric acid I) 2.8 2 0.1 4.9 2 0.2 10.5 < 0.001 @gld I UNIVERSITY OF IBADAN LIBRARY Prevalence of Zn deficiency was 4% in the non-pregnant population while it was 22.5 % in total pregnant state, but increased to 10% in the 1'' trimester, to 20% in the 2nd trimester to 33.3 % in the 3d trimester (table 47). This observation is important and probably alludes to suggestions that Zn, like Fe and folate should be given as supplement in pregnancy. Taken together, these data, suggest that oxidative stress is pronounced in the pregnant state probably from Free radical poisoning and that micronutrien ts supplementation may play an important role as antidote. Considering their role in pregnancy, prevention of deficiency arising from increased demand and attendant oxidative stress may contribute to a reduction in the incidence of foetal and maternal ill- health and complications in pregnancy. W e recommend that intervention should be mainly directed at the second and third trimestek. Tabb 47: Comparison of Serum Levels of Micronutrients and Uric Acid in Pregnamt and Noa-pregnant Women tn the Three Trimesters pregnant Trimeter T m e r Trimester Cu(&dl) 137.4 * 5.8 185.6a10.8* 220.4k7.8' 220.4k7.9 Mn(q/ml) 10Ak0.7 7.4 * 0.9W 8.4 s 0.5 9.9 * 0.5 Za (pg/dl) 97.4 ;t 2.6 95.2 k 4.5 92.1 k 4.4 83.3 4.5 Uric acid 4.9 0.2 1.9 k 0.2" 2.0 k O.l* 3.0 k 0.2 (WW) Values are mean * SEM *Significant at p< 0.05 An adequate evaluation of micronutrient status may help in assessing risk of maternal morbidity and mortality probably in part attributed to oxidative stress. This has tended to be restricted to iron and folate in the past (Rooney 1992). The practice should be extended to other micronutrients such as Cu, Mn, and especially, Zn which is central in the metabolism and bioavailability of other rnicronutrients, such as vitamins A and E (also antioxidants) as well as nucleic acid metabolism that are very essential for matemal and UNIVERSITY OF IBADAN LIBRARY foetal health (table 48). Optimal micronutrient status (thus adequate antioxidant status) may contribute significantly to a reduction in the incidence of ill health and many life- threatening complications of pregnancy that are still common in many developing countries. Indeed, giving priority to antioxidant micronuhients status in pregnancy in Nigeria may be an additional weapon (prophylaxis; antidote) against the distressing maternal morbidity and mortality rates in Nigeria and other affected countries. Table 48: Prevalence of Zinc Dffieieney in the Pregnant and Non-pregnant States Subjects Number of Women Pemmhge (%) of women with low Zn level* with low Zn levd* N o n - p v t( n= 25) 1 4.0 AU pregnant women 9 (m * A low level is defined as that b l o w the lower limit of reference range Pregmmq &d Cadmium Poisoning: Ameliorative Potentials of Essential Trace Elements ( E m ) Cadmium is currently of great concern as it is rising in rapidly industrializing countries, especially India, China and by extension, Nigeria (Yan 2006; Sun 2007). Our study on cement dust (Ogunbileje et al. 2013) and the increasing number of cement factories suggest this may be also be a source of significant Cd contamination among others. Cadmium-products are in increasing demand and consumption with concomitant increased waste laden with Cd that may contaminate the environment (Bakare et al. 2008). It is thus a ubiquitous environmental pollutant to which humans are increasingly exposed. Though scattered reports suggest that Cd may be associated with the delivery of low birth weight (LBW ) babies, the mechanisms, possible amelioration UNIVERSITY OF IBADAN LIBRARY and implications for the already high maternal and child mortality rates had not been addressed. We examined 160 individuals comprising of 125 pregnant and 35 non-pregnant women. We classified the pregnant group into, the traditional three trimesters of pregnancy. The last (third; 55 participants) trimester was followed up till delivery. The following were the key findings (tables 49-52): 7% gave birth to high birth weight (HBW) babies. 58% of the pregnant women gave birth to normal birth weight (NBW) babies. .e 35% gave birth to LBW babies. Remarkably women with LBW babies demonstrated higher Cd and lower, Fe, Zn levels and BMI (It is again important to draw attention to this). LBW babies exhibited smaller head circumference and shorter length inversely correlated with Cd level (tables 50 & 51) (Ikeh-Tawari, Anetor and Charles- Davies 20 13). We concluded that environmental pollution be borne in mind in regions with persistent low birth weight babies and that supplements with essential trace elements such as Fe, Se and Zn may play ameliorative roles. These appear to be the new remits for the contemporary Chemical Pathologist (risk assessment in clinical care). UNIVERSITY OF IBADAN LIBRARY Table 49: Conrparisom of Demographic Xadices, Anthropometric Measurements and NutrItiona~ Parameters of Noa-pregnant and Pregnant Subjects fn I*, z*, and 3d Trimesters Parameter NP(n=35) 1n"4 2m TZU 3mTRI . ( 5 T RI a= 35 1 (n= 5s) F-v alue p value ) ( Cd (~moV1) 0.22 i0 .1 0 .2M.1 0.2 IM.1 0.25a.1 3.478 0.017' Zn (pmoM) 11 .7 k 4.3 1 1.4a.9 1 1.322.7 10.4 * 2.4 1.407 0.043* Fe(wV1) 26.9 * 6.5 23.7 rt 6.6 25.9 & 6.2 23.6 * 5.6 2.742 0.045 * Cn(pamyl) 14.4d.7 14.9 k 3.3 15.4 * 2.1 16.8 * 3.6 3.190 0.023* Se(lum,M) 3.5k0.8 3. k 4 0.7 3.5 k 0.7 3.4 * 0.8 0.126 0.945 T. Prot,(@) 60.9 k 1. O 64.0 & 0.9 58.0 * 1.2 63.0* 1.2 3.487 0.017* Atb. 39.0 * 0.9 35.0 * 0.7 32,O rt: 0.7 33.0 * 0.8 8.097 0.000* Age (yemrs) 28.6 i 7.1 28.6 & 5.7 29.4 & 4.9 29.5 * 6.5 0.336 0.871 2.0&1 .6 2.1 & 1.6 1,9 * 1.7 2.2 1.5 0.236 0.671 ~ ~ ~ ( k p l r n25~.3) * 3.6 26.k 4.9 27.6 i5 .4 28.7 * 1.5 0.997 0.039* *Significantly different at indicated levels, NP = Non-pregnant, TRI= Trimester, BMI= Body mass index Source: Ike-Tarawari (2013 ) UNIVERSITY OF IBADAN LIBRARY Table 50: Third Trimester Maternal Indices of Women with Low and Normal Birth Weights Babies Low Birth Normal Maternal I n d i c ~ Weight Birth Weight (n=19;3 5 %) (n=32; 58%) t- value pvalue c d ( WOW 0.03 0.0 1 0.02 & 0.01 7.9 18 0.01 7* zn ( ~ 0 f l ) Fe (POM) cu (WOW Se (POW , Total protein (@I) Albumin (gA) Age (years) Parity BMI (kg/m2) *Significant at levels indicated, BMI = Body mass index Table 51: Neonatal Anthropometric Measurements of Babies with Norm1 and Low Birth Weight Normal Birth LWoewig hBti rth Parameters Weight (nd2; t- value p- value 58 %) (n= 19; 35 %) Birth weight (kg) 3.1 & 0.4 2.2 -i. 0.3 6.952 0.000" Head circumference 34.6 * 3-8 32.3 A 2.2 2.675 0.010* (cm) Length (cm) SO. 1 3.6 46.6k3.4 3.818 0-000" *Significant at the levd indicated Table 52: Correlation of Third Trimester Maternal Indices with Neonatal Parameters Normal Birth Head Maternal Indices Weight (r, p- Circumference hn%h ( r, P- vaiue) (n S S ) (r, p- value) (n= 55) value) ( n= 55) c d (POW -708,O- OOO* - 0.332.0.01 3" -0+499,0.00I * Zn (~lmom) 0.306,0.023* 0.225,0.039* 0.242,0.036* Fe (POW -0.192,0.160 -0.161,0.241 0.1 57,0.24 1 cu (WOW 0.022,0.872 O.WO,0.901 0.066,0.634 Se (POW -0.305,0.023* -0.11 6,0.399 -0.357.0.058 BMI (kg/mX) 0.78 I , 0.000* 0.537,0.000* 0.488.0.000* * Significantly different at indicated levels. Sourc~I:k e-Tawari (20I 3) UNIVERSITY OF IBADAN LIBRARY Cancer as Chemical Poisoning: A Call for Education Prevention of poisoning requires sufficient knowledge of the hazard of the substances by the users. This is very important in industrializing countries. As we have seen in a number of our studies workers may present chronic poisoning as in metal workers, such as welders or radiator repairers. Central nervous system damage from pesticide exposure may also be evident (Anetor et al. 2001d). While in the advanced countries employers have been mandated to adhere to details of occupational exposure requirement for the use of protective devices these safety requirements are hardly observed in the developing countries, thus higher exposure intensity are expected. A sizeable proportion of the present incidence of cancer appears be the result of chemical carcinogenesis (cancer from chemical exposure or poisoning ). The estimates vary, ranging from as low as 4% to as high as 60% or more (True and Dreisbach 2002). I am not sure if developing countries' specific estimate has been conducted. In the United States, the Occupational Safety and Health Administration (OSHA) has established nil or zero leveis of tolerance in work environments for many substances including chemicals suspected to be carcinogens to humans. We need to do the same (educate) in Nigeria part of the detoxification process. In addition to this all individuals should be familiar with the concept of risk versus benefit in using chemicals everywhere, at home, in the work place or in the environ- ment. Workers who use toxic substances that generate aerosols must be advised to use well- fitted respirators with organic filters, not simple dust masks that are insufficiently protective (True and Dreisbach 2002). Importantly also, people should know that there are no safe chemicals but only safe ways of using them. Consequently, all dangerous medicines, including aspirin, soluble iron salts, and a1 1 house hold chemicals should have poison labels on them. This is particular1 y important in our country where the literacy level is still low and many drugs can be purchased over the counter UNIVERSITY OF IBADAN LIBRARY with ease. We investigated the contribution of a common poisonous substance to a common cancer, liver cancer. Arsenic Poisoning and Hepatocarcinogenesis (Liver Cancer) Arsenic is one of the highest priority hazardous substances around the world currently and is well known for its toxicity and carcinogenicity in humans (National Research Council, 1999). Meth ylation of inorganic arsenics is an importantn step during the process of their elimination in many mammals. Generation of monometh ylarsonic acid (MMA (V)), monomethy Iarsonous acid (MMA (III)), dimethy larsinic acid @MA (V)), dimethylaminous acid @MA (111)) and trimeth ylarsine oxide (TMAO (ID[)) is as a result of the action of the enzyme meth yltransferase, a reaction requiring S- adenosinemethionine (SAM). Dimeth y larsinic acid @MA) (V) is a major metabolite of organic arsenics in the environment and the main metabolite of ingested inorganic arsenicals in most mammals including humans (Goering et al. 1999; Kitchen 2001; Bramans and Foreback 1973). DMA (V) itself is used as herbicide and pesticide and also naturally exists in some sea food. Studies have revealed that DMA (V) is a genotoxic, multi-site promoter of carcinogens in rodents (Yamanaka et al. 2001). Thus providing a novel clue to investigate the mechanism of arsenicals in carcinogenesis. Currently, millions of people all over the world are exposed to this ubiquitous toxicant at exposure levels leading to long-term toxicity, particularly cancer (Basu er al. 2001; Gebel et al. 200 1 a). Epidemiological studies have indicated that populations exposd to high levels of arsenic are prone to develop liver, bladder, skin and lung cancers (Chiou et al. 2001). In addition to its carcinogenic effects, arsenic exposure has been suggested to play a role in black foot disease (a form of peripheral vascular disease) (Tseng et al. 1996), type II diabetes mellitus (Tseng et al. 2000) and cardiovascular disease (En gel et al. 1994). Cancer of the liver is an important member of the various types of cancer associated with chronic arsenic ingestion from epidemiological evidence (IARC 1987). This is of major public health significance as UNIVERSITY OF IBADAN LIBRARY over 200 million people are exposed to inorganic arsenic in drinking water in many countries of the world. Animal studies have revealed that the liver is a major target organ for toxicity, being the organ most involved with the detoxifi- cation of xenobiotics and also the main storage site for glutathione (GSH), the cell protectant antioxidant against oxidative damage and other insults to the liver as well as the vital organ for methylation of inorganic arsenite mealy et al. 1989). There is dearth of data on the initiation ac&ity of dimeth ylarsinic acid @MA (V)), the major metabolite of this ubiquitous environmental and occupational carcinogen and toxicant. The initiation activity of DMA (V) was investigated on rat hepatocarcinogenesis; the liver being the major target organ for arsenic carcinogenicity and toxicity. A total of 50 rats at 10 weeks old were randomly divided in a 9-week medium-tern bioassay into four groups (fig. 16). Groups 1 and 2 received 200 ppm of DMA (V)i n drinking water for 4 weeks while groups 3 and 4 drank only tap water until the 6" week when groups I and 3 were given 0.01% 2- acetylarninofluorene (2-AAF) in diet as promoter for 2 weeks. All animals were subjected to two-third partial hepatectomy (PH) at the 7'h week. Quantitative analysis of gluta th ione S-transferase placental form (GST-P) positive foci in liver, preoneoplastic makers of rat hepatocarcinogenesis demonstrated higher numbers in group l@MA(V) + 2-AAF) than in group 3 (ZAAF alone) at foci consisting of 2 4 cells and 15 or greater number of cells. The number of GST-P positive foci consisting of 5-9 cells was significantly higher in group 1 than in group 3. Figure 16 shows the experimental design. Foci consisting of 10-14 cells were also higher but not significantly. While GST-P positive foci were apparently similar in groups 2 and 4 @MA (V) alone) and (untreated group; control) respectively. Expression of total GST-P positive foci was significantly higher in group 1 compared to p u p 2, 3 and 4 respectively. The proliferating cell nuclear antigen (PCNA) test performed to clarify the apparent trend of GST-P data revealed significantly higher PCNA labelling index (LI) in group 1 (fig. 17). These data are consistent with weak or initiation potential of DMA (V) and appear to UNIVERSITY OF IBADAN LIBRARY provide for the first time evidence for the initiat~ona ctivity in DMA (V)-induced hepatocarcinogenesis in rats and call for caution in holding on rigidly to the existing paradigm that DMA (V) is only a promoter by modulating the signaling pathways responsible for cell growth, until additional data or confirmation of the present study are available (Anetor et al. 20076). This study has great implications for this environment in that a lot of food is imported from Asia where.arsenic is currently a major problem. Additionally, the mitigation of arsenic poisoning requires adequate supply of GSH derivable from protein, which may be grossly inadequate in population. with compromised nutritional level including MDDs. Thui even low As level may have magnified effect. A number of our studies have repeatedly demonstrated this. Fig. 16: Experimental design. Animals: Male F344 rats, 10 weeks old Tet chemicals: DMA (V): dimethylarsinic acid; 200 pprn in the drinking water. 2-AAF: 2-acetylaminoftuorene;0 .01% in the diet V, PH:2 3 p artial hepatectomy at experimental week 7 Examination: GST-P PCNA After Anetor et al. (2007d) UNIVERSITY OF IBADAN LIBRARY Fig. 17: PCNA indices in rat livers, significantly different from control group ( p u p 4). '~ignificantl~d ifferent from 2-AAF group (group 3). Studies on Chronic Obstructive Airway Disease: Asthma Asthma, one of the commonest chronic obstructive air way diseases was previously considered rare among Africans (Ayers 1995). But it is now known to be common (probably paralleling the degree of pollution in the environment due to progressive industrialization) but poorly managed (Unwin and Alberti 2000). Studies have shown that inflammation in the bronchi plays an important part in the aetiology. and development of bronchial asthma ( B m e s 1991). Mounting evidence indicate that the allergic disease asthma is caused by a flaw in the free radical-antioxidant balance (Soutar et al. 1997; Kelly et d. 1999). Indeed free radicals (chemical species with unpaid electrons in the outer orbital) are now known to mediate the inflammatory process so characteristic of asthma (Kelly 1999). Increased environmental pollution or environmental poisons was in the past blamed for the global prevalence of asthma thought to parallel industrialization. Though this has declined in the advanced countries like the United Kingdom UNIVERSITY OF IBADAN LIBRARY and the United States, pollution is today a prominent part of the environment in many developing countries including Nigeria. The question has been asked whether the increase in the prevalence of asthma and bronchial hyperactivity is due to a more toxic (poisoned) environment or a more susceptible population (Seaton et al. 1994). For our environment both sides of the question may be operative; antioxidant are mostly micronutrients of which many populations in the developing world are deficient (Gibson 1994; Underwood and Smitasiri 1999). We thought that it was good news that antioxidant modulation of asthma implies a role for nutritional intervention and points the way to a means of reversing the upsurge of this disease. We considered that while the medical and scientific communities appeared to be awakening to the potential benefits of using antioxidants to ameliorate (prevent, manage and reverse) asthma its implication for prognosis that had received no attention should be addressed. Fifty asthma patients, adopting an approximately one in ten random patients of all asthmatics registered at the Allergy Clinic in the Medical Out Patient (MOP) department, University College Hospital, Ibadan were selected. They were classified into two groups; moderate and severe cases, largely based on the Level of distress according to the criteria of Eric and Halpren (1994). I am glad to report (Anetor, Ajose, Ige et al. 2003) (tables 53 & 54) that significantly lower levels of magnesium and key antioxidants, vitamin C,a lbumin and uric acid were found in asthmatics. The very substantial reduction in vitamin C level compared to non-asthmatic (or controls); in this study; over 260-fold is noteworthy (table 53). Surprisingly, the anti-oxidant status did not differ with severity of the disease except for urate level which was up- regulated in the severe group (table 54). Our findings suppofl and extend the emerging concept that antioxidants are consumed in this inflammatory disease which we have demonstrated to have a significant toxic component and that a corresponding increase in antioxidant supply may improve ' prognosis; also that this may at least in part be the scientific explanation for the varied responses to therapy by patients with this disease. UNIVERSITY OF IBADAN LIBRARY Table 53: Serum Albumin, Copper, Magnesium Uric Acid and Zinc Levels in Asthmatics aod Noriaasthmatics Asthmatic (n=50) Ncno=n2-5a)s thmatia tValue p-value Mg(mmoVf) 0.76k0.03 1.09*0.02 4.66 < 0.001 Values are mean A SEM Table 5Q: Serum Mapsiurn, in Copper, Zinc, Vitamin C, Uric Acid and Albumin Levels in Groups I (Moderate) a d 2 (Severe) Patients Group 1 Fnm=1?4 &vr dmuee p-value Cn==ww (n=14) Mg [-MI 1.0 A 0.04 0.99 + 0.62 0.54 >0.05 Values are mean * SEM Hydrocarbon Poisoning: Benzene Nigeria for a long time has been a major explorer and exporter of petroleum products from which petrol is obtained and associated hydrocarbons derivatives. One of the commonest of these is knzene which is implicated in the bone marrow disorder, leukaemia. The mechanisms and modulating factors have only received limited attention. We investigated petrol dispensers who are exposed to benzene on a regular basis, using the major metabolite of benzene, phenol (fig. 18). Our results suggest as follow (fig. 19 and table 55): UNIVERSITY OF IBADAN LIBRARY Fig. 18: Pathway of benzene metabolism. - Lu brfrll . PI Drlll- 4 - - -l. zn tbc-t lp- Y**: bull1 PL*rrl.. _L.U -d@p, I - - .- - - Fig. 19: 'Level of phenol and micronutrients in chemical workers. UNIVERSITY OF IBADAN LIBRARY Table 55: Correlation of Phenol with Micronutrients, Haem and Duration of Exposure Unexposed Correlating Variables Gasoline Dispensers participants (Control) Age vs Duration of exposure (Yrs) Duration of exposure vs Phend Age vs Phenol Phenol vs Fe Phenol vs Eaem Phenol vs c u Phenol vs Zn Duration of exposure vs Haem Duration of exmmre vs Zn -. -- Values are mean k SEM Marked perturbations of the haemopoietic system resulting from benzene toxicity is suggested in these gasoline dispensers. The major mechanism in part, seems to be a drain on the key micronutrients in this pathway; Cu, Fe and Zn, which play very important roles in the antioxidant defense system, Cu-Zn SOD and catalase and vital molecular activities. A1 tered xenobiotic metabolism requiring haem in cytochrome P450;c ell cycle dysregulation where Zn plays a key role and p53 suppression also dependent on Zn may all co- exist in these chemical workers. Importantly, depression of the levels of these key micronutrients implies potentiation of myelotoxicity and myeloproliferative disorders arising from alterations in transcription, replication errors, genome instability and derangement in cell signal transduc tion all of which may raise the risk of carcinogenic potential in this pathway, the commonest of which is leukaemia. Understanding this benzene-induced pathobiology may be important in risk assessment, policy formulations and regulatory safety measures in these chemical workers and the general population (Anetor, Adigun, Bolajoko et al. 20 15) The Electronic Revolution: A Blessing or a Scourge? There is no doubt that the explosion in the electronic industry has greatly enhanced communication, contributed to welcome UNIVERSITY OF IBADAN LIBRARY surge in economic activities, improved the quality of life, security but sadly has raised the scope, magnitude and frequency of crime. Where the concern of toxicologists really rests is the afterlife of electrical and electronic devices, they become a huge problem, which though occult to the lay public is worrisome to scientists. The huge electronic waste generated, most of which is shipped to the developing countries as second hand (tokunbo) as evident in figure 20; may be another way of chemical colonization; getting rid of waste in the advanced nations and dumping them on the resource poor recipient nations. Expectedly, Nigeria is one of the leading.dumping sites of used electrical and electronic waste. You may ask me why are they of concern? They contain many precious metals that scavengers are searching for as well as abundant toxic ones such as Cd, Pb, As, Hg to mention a few. Again we are lucky in this university to have had one of the leading world experts 'in this university, Professor Oladele Osibanjo. With his team from the Base1 Convention Coordinating Centre (BCCC) they have consistently reported that E-waste is becoming a big problem. But just like when the issue of climate change started their lamentation has fallen on deaf ears. Fig. 20: E-waste pollution. Source: The Conversation, August 19,2013. UNIVERSITY OF IBADAN LIBRARY . To investigate the possible human health effect of E- waste a Ph.D student, Mr. Godwin Igh-aro, a lecturer at the School of Basic Medical Sciences, University of Benin is cumntly working on this. I invited Professor Osibanjo to join in the supervision of this student, he kindly consented. This very ' hard working and productive doctoral student has generated data that have resulted in four papers so far that are very instructive and disturbing. Expectedly he has confirmed extremely high levels of the key + toxic metals in E-waste workers (Igharo et al. 2014). More importantly, the data suggested more serious health problems such as liver damage . (Igharo et a]. 2015a), increased risk of liver and prostate cancer (Igharo et al. 2015b) and putative mechanism of evolution of these disorders, oxidative stress among others (Igharo et al. 2016). These mults demonstrate the magnitude . of the health problem that is unfolding and will continue to increase and call for collective action now. Concluding Remarks and Recommendations Mr. Vice-Chancellor, Sir, I have attempted to show that we are poisoned from various sources and agents from our polluted environment, from the drugs we. use, from endogenous metabolism including the metabolic processes associated with pregnancy and several more.'~hish as led to ' .the overthrow or disruption of the normal levels and relationships of the chemicals of life with dire consequences that set in insidiously. My conclusions will essentially be a , summary of some of the reviews of some of our studies highlighting these lesions and suggested approaches to restoring physiological state or their mitigation. Let me start by saying that we have been like prophets; in 2000, it was clear to us that the ~fricahe nvironment, using Nigeria as case study was poisoned with lead In an article entitled 'Lead poisoning in Africa: a silent epidemic' (Anetor and Adeniyi 2000), we warned that there was wide spread lead poisoning and appealed to the African Union (AW) to set up centres of toxiwlogy because of the cost involved in setting up toxicology services that many poor African countries cannot b - - - --... .w - I I m ~ w ~ i ~ ~ ~ - : r - b - ~ q q:r~i -p ;- 3 I. --- --. r , . . . 1 ~ . l > . I--. 1: I I A r ~ ~ r Tl . ~I I - c .- . - UNIVERSITY OF IBADAN LIBRARY afford. Shortly an outbreak of Pb poisoning was reported in Dakar, Senegal, then from Nigeria; the now globally recognized Zamfara lead poisoning, then Niger state and several unreported cases that are considered mysterious diseases. For me these are only tips of the iceberg. Nriagu et al. (1996) corroborating our view, had reported that over 90% of the children in Africa are poisoned with lead (BLL greater than acceptable levels; circa 2pgfdl). Based on our studies we made another pronouncement that is very germane to the theme of today's discourse. Industrialization and increasing risk of genome stability in developing countries: nutri- genomics as a promising antidote (Anetor 2008), suggesting genome protective nutrients acting at molecular level were needed to mitigate the situation. Further in another report; education in micronutrients in primary healthcare as prophylaxis for environmental pollution and disease (Anetor 2000a) we recommended that rnicronutrients were antidotes to environmental disease. We have also suggested that anti- oxidant micronutrients are inter-sectorial link between health and agriculture (Anetor et al. 2005). We argued for a functional partnership between the agricultural and the health sectors, with the agricultural sector mainly producing the sources of the rnicronutrients, embracing soil analysis to subject polluted farmlands to bioremediation to ensure that the micronutrients from plant and animal sources yield antioxidants that are contaminants free and will ameliorate poisoning, promote damage repair and boost host resistance to poisoning or toxic states. I have maintained that antioxidants if the proper ratios are ensured after scientific investigations are a veritable tool against cancer, other degenerative pathologies and toxic states (poisoning) (Anetor 2009b). The WHC) Report 2011 identified some key micro- nutrients (iron, vitamin A and zinc) among the world's most serious health risk factors. Micronutrient malnutrition (Microputrient Deficiency Disorders, MDDs) contributes to a vicious cycle of poor health and depressed productivity, trapping families in poverty and eroding economic security in many countries worldwide (Anetor 2000). Ensuring adequate intake of these essential nutrients by vulnerable populations UNIVERSITY OF IBADAN LIBRARY (mainly women and children) will offer enhanced protection against various forms of poisoning, whether endogenous or environmental, children will grow and learn and improve the health and productivity (including reproduction) of women. - This appear probably congruent with the observation of Gey (1986), a former Chief Nutrition Officer of the WHO, that if the key antioxidant levels; vitamins A, C, E, P- carotene, selenium and zinc levels are low, the risk of the population contracring cancer or cardiovascular disease is very high. Similarly, the Japanese during the heart of their industrial development incmed intake of nutri tiond factors like vitamin E abbut ten-fold the RDA as protection against environmental pollution. My own argument is that the level of a chemical toxicant should not be used solely as the index of poisoning. Even when the toxicant is low or marginal as we have demonstrated, the key protective factors such as, Zn, vitamin C, Se, Mg, vitamin A, vitamin E, pcarotene and others suck as GSH, if deficient or low the manifestation of poisoning is certain and that in the converse situation the organism or human will be prutected. Figure 21 is an example of good sources of protective nutrients. On a global level we have. presented arguments that poisoning by such toxicants as metals can be mediated by rnicronutrients. The case of zinc as borne out from our data is particular1y striking. Thus we have affirmed that mimnutrients are host resistance against toxic states (A netor, Wanibuchi and Fukushima 2007). It is undoubted that the Nigerian environment is increasing1y toxic and that the population is concomitantly susceptible to poisoning owing to the unsung but real problem of hidden hunger or MDDs; thus the advice smarized in one of my reports- 'The increasingly toxic Nigerian environment and an increasingly susceptible population: a challenge to scientists in laboratory medicine and biology' (Anetor 2014) is relevant. The need for assessing of micronutrient levels in at risk populations as a step in risk assessment appears relevant. Another of our report that may be useful in closing this discourse is the one on the Zamfara lead poisoning entitled, 'The Zamfara lead poisoning episode in Nigeria: An UNIVERSITY OF IBADAN LIBRARY indication for children' s environmental toxicology and micronutrient centre' (Anetor et al. 2016a). Most of the conclusions and recommendations remain very relevant. In the same vein, very recently, we have shown (Adeniyi et al. 2016) that zinc modulated immune response in toxic states in occupational groups. Oxidative stress was amply demonstrated as a major mechanism in our poisoned subjects, suggesting a role for 'antioxidantsa s possible antidotes. Generally, nutritional science is being .i ncreasing1y recognized as having new and special roles in environmental toxicology and a major determinant of host resistance to susceptibility to chemicals in the environment (Anetor, Wanibuchi and Fukushima. 2007). The impohce of nutrition and its effect on susceptibility to development of poisoning is becoming better understood, and poor nutritional status apparently can greatly increase chances of poisoning like newtoxicity as we have demonstrated in a number of our investigations. Nutritional factors influence the toxicity of many environmental pollutants, such as pesticides (common in developing countries) and toxic metals as we have consistently confinned in our laboratory. W e H im that the concept of nutritional modulation of chemical toxicity is an important one, and one that should be exploited to the fullest by scientists and physicians. Taken together and recognizing the usual uncertainty associated with science, I unequivocally state that the antidote we have found against current overt and occult poisoning of the world is the use of the micronutrients, which work as receptors, co-factors, co-enzymes, signal transducers, transcription factors, immune response enhancers and antioxidants). They restore the chemicals of life to their proper levels and order including genome stability, a precursor of the carcinogenic state, thus assisting in unpoisoning or serving as antidotes to our contemporary poisoned world. Though several aspects of chemical toxicity or poisoning are still unresolved based on weight of evidence, the precautionary principle is advocated to avoid late lessons from early warnings &d should be one of the highest research priorities of developing countries. UNIVERSITY OF IBADAN LIBRARY * arad V~etaMtlsa s aa.lu m, 3.t w murcm. c o w m y 0.a Qgmdipet MmB I &bf ~ - m Iy will be~ failing~ in my ~ ~ ~ t 'Wty as a lqemho f& *M JWaknic co-v =not wmimnt an the tmdcityfhst cmnt ly exists in a~iw&&m in N i g d i We q p a r to have fmgatkn our wpamihi&y to swiety w w ~ ~~e of the Ttimgl~N ath C a t o w H t e d a s follows: The aeedemi~c ~ m u n i t yis the principal generator, iinteptar, dissmdmt~ra nd weirall cwt&iannof knw1edp9 (Malone 1993J This is a great mpmibility which we iqpar to be Wng lightly by what I call inamsbg toxicity to each uther and the very mscb1arly attiwle noG very rampant. 1 have i*hradm his slsewhem paticu1wly the shameful ajtvnim ( in the.h ealth sector (Amtar and Oyedele 2016) in a book pja by the Olusegm Obsmja hesidmtial Li-, Towards a Pllew D mFo r The Health S W id~ N igeiia Post 2015'. I was privileged a0 h m b een invited by Pkufw 0.0. Akinkugbe, a cmc& elder m d i ~ aml , tts one of the redcwersbf the repact. It k a hndmwk mpr t I enjoin all to try and raad (fig. 22). UNIVERSITY OF IBADAN LIBRARY m*22 : Mi with the tusi'w among academics' and Mth care . p ~ u ~ s ; It ie perhaps propa to examine what happens in same pmgmssive m%m8. Rum Brown Univmity eoms @e following, The W m a pt W c a l School of Brown ~ n i v d~tar~n pxkaa d l _ m t t y o f &olm ddi~atedto the highe%t smdwb d exdlent education, msamh, and healthcam Our miasion is to impat to future physicians and scientists tbe state of the art af the scientific, ethical and hmmbtic dixwmiotls of medikd sciacle and of public health', How do we fit in? UNIVERSITY OF IBADAN LIBRARY 'The qualily of our research can only be as strong as the foundation upon which i#r ests' - Robert Berdahl, President, Association of American Universities. 'And if the fundamental operations of our research universities are deteriorating the country's research superstructure will inevitably decline as well.' (Ibid) What are ;he= fundamentals? How do they play out here? From the University of Leicester I picked what I consider very inspiring and worthy of emulation in U.L: 'Elite without Being Elitist' We think a university should be about empowering people to explore what they do not know; through passionate, dedicated teaching and innovative, world class-changing research. By embracing the fact that we are all coming at it from a slightly different place, and that every journey is personal, we have managed to achieve some remarkable results in our time. We believe that the best universities are not just the privilege of elites. We're proof that you can stand alongside the best and open up the competition for everyone. Some universities consider their primary purpose to be high quality research, others concentrate on excellent teaching. At Leicester we think that the two are not only complementary, they are inseparable. We believe that teaching is more inspirational when delivered by passionate scholars engaged in world-changing research- and that research is stronger when delivered in an academic community that includes students. With these ideas at heart, Leicester is refrdng the values that govern academia and redefining what a university needs to be in the 21'' century. We are constantly finding new ways of being a leading university". Can we say the same of us? What I see, is that instead of emulating these laudable goals we are increasing1y toxic to each other. Aside from my UNIVERSITY OF IBADAN LIBRARY research I had informally set myself the task of det~xifying our own toxic academic environment by deliberately absorbing whatever happens and enthroning desirable practices in refined societies. This has to be addressed if we are to attain true greatness. Let us embrace true scholarly principles. The situation now, particularly in the college is that academics have been virtually reduced to trade union activities. Even if this happens in other universities in Nigeria, University of Ibadan should resist this tendency of 'crush others by the privileged' group. Let us like Linus Pauling, a double Nobel Laureate pull the best from which ever field to build an enduring and effective system. Let us place the institution and benefits to society first above our personal leaning. Linus Pauling would bring the best from any field and collaborate with them and put California Institute of Technology (CalTech) first. He went from chemistry to nuclear physics, medicine, particularly micronutrients or orthomolecular medicine. His state manly approach to science and global peace was rewarded. Once our intention is right, like Linus Pauling the benefits and fulfillment will be long lasting long after we have gone. Right now what appears operative is 'my Mercedes is bigger than your own'; these thoughts are for little minds. Genuine academics are broad minded and discuss ideas not people or material. Let us make academics what it truly is. Academics is the hope of the world, I am very proud and happy to be a scientist, a scholar, a member of the academic community. It is the highest any one can aspire to be, let us not destroy it in this country. After God the scientific or academic community is the last port of call. We have seen this play out in many situations. Let us be genuine members of the academic community, not a 'Nigerianized' one. There are some great scientists I have selected as my mentors over the years; Linus Pauling, Peter Medawar, Richard Feynrnan, Bruce Arnes, Leon Goldberg, David Linn Edsall, (the first full time Dean of the Harvard Medical School) who made Harvard medical school what it is today, a home for all. Why cannot we make Ibadan medical school the same? UNIVERSITY OF IBADAN LIBRARY Recommendations Mr. Vice-Chancellor at this point what comes to my mind is need for translational research or in this case translational medicine in today' s poisoned world. Translationa 1 medicine focuses on the conversion of basic biomedical research into practical applications, thus bridging the research-to- application gap (Bench-Bedside). Trans-lational medical research is increasingly recognised as important to the national health service of many nations. There should be focus on translational medicine and both clinicians and scientists should work in collaboration to mitigate the health effects of inevitable chemical poisoning. Translational medicine provides a means for the rapid translation of discoveries in the laboratory into clinical practice. The astonishing advances in understanding the fundamentals of life have not translated into equally astonishing improvement in human health. This observation was indirectly what led to the establishment of the National Academy of Science (NAS) of the United States of America. On March 3 1836, President Abraham Lincoln signed an act that established an independent corporation to "investigate, examine, experi- ment, and report upon any subject of science or art", when ever asked to do so by the American government. Thus in the middle of the civil war the National Academy of Science was born, an admirable scientific body that has served the American nation, and indeed the whole world creditably. lntemtingly more than a century later, precisely, 23 March 20 10, another American President, President Barack Obama signed a landmark health care reform bill that, among many other issues created another agency - the Patient. Centred Outcomes Research Institute (PCORI) - to carry out a much narrowly defined but focussed scientific mission. In line with the broad objective of translational medicine, PCORI's purpose is "to assist patients, clients, users, and polic y-makers in making informed health decisions by advancing the quality and relevance of evidence" regarding ways in which a broad range of health conditions can be UNIVERSITY OF IBADAN LIBRARY "prevented, diagnosed, treated, monitored, i d managed through research evidence synthesis and conside& variations in patient subpopulations". This non-governmental agency is also charged with "dissemination of research findings with respect to the relative health outcomes, clinical effectiveness, and appropriateness of medical treatments, services and items. The ultimate goal of PCORI is to improve patient outcomes 'by using the best clinical technology, techniques. and medications in existence, as determined by the besl available research evidence. This is what we need tc ameliorate chemical poisoning that will worsen with diversification of the economy with increasing attention to the mining sector. Scientists must be at the frontier of a similar effort in Nigeria. The Agency for Health Research and Qualiy (AHRQ) and the National Institutes of Health (NIH) of the United States have rightly applauded the establishment of PCORI and states that it will build on their agencies' long standing investment in Comparative Effectiveness Research (CW)t o provide well validated evidence- based approaches to medical care that can improve patient care. Comparative effectiveness research is designed to inform health care decisions by providing evidence related to the effectiveness, benefits and harms of different treatment options for a given condition, including subgroups within that condition. The evidence is generated through research that compares drugs, medical devices, tests or investigations, surgeries or methods to deliver health care. This principle appears particularly relevant to chemical poisoning considered one of the greatest health challenges that face the global community (WHO 1992). It gives scientific base to the nation's health care system. Scientists are dispmportionately charged to use science to improve the nation's health system as enunciated by Laurer & Collins (20 10). Are we doing this or are there impediments? If we put impediments in the way of scientists, then we will be unwittingly contributing to the disturbing prevalence of poisoning and its implications, manifesting as cancer, birth defects, increased susceptibility to common UNIVERSITY OF IBADAN LIBRARY disease (due. to immunosuppression) increased crime rates, declining academic performance in our schools, increased allergies and asthma, accelerated aging including baldness and precocious death. Our life span is put at about 55years; chemical poisoning cannot be ruled out as a major contributor through the mechanistic pathways enunciated above. To be more effective in translational medicine in Nigeria, we need a body similar to the NM of the United States, which is a recognized leader in supporting CER studies that develop primary evidence of effectiveness, including comparative clinical trials and support for accelerating the path toward personalized medicine. Together with AHRQ, the NM in America is uniquely positioned to draw on decades of research experience to help PCORI establish its organizational structure, formulate its methodological standards and develop research priorities and processes. In the absence of NM like bodies in Nigeria, I see no reason why professional regulatory bodies in the country cannot forge this partnership rather than proliferating other resource guzzling ineffective institutions as we have it in Nigeria today and fighting themselves. The statutory regulatory bodies of the Nigerian health system should participate in the fashioning of a robust portfoIio of scientific enquiry that builds on current and prior federal research and that remains focused on improving the end result of patients. A striking feature of the bill establishing NAS is its slim volume, suggesting that legislative length is not always a good measure of a research organization's potential impact on society. Just as it took a dedicated crop of scientists to fonn what evolved in to a venerable academy to advise the United States on matters of science, Nigeria today stands in need of scientists willing to devote their time and energy to tackle the impact of chemical poisoning in an increasingly susceptible (malnourished) population. This is absolutely vital to the nation's health care system. This should be a joint effort in the name of science for health reform and science in the service of our society or nation. Owing to the threat of chemical poisoning it is more than ever before mandatory to UNIVERSITY OF IBADAN LIBRARY strengthen the nation' s health system, including laboratory services to avoid nationwide repeat of the Zamfara episode of lead poisoning of 2010 which is actually still lingering. This view is truer today in the face of the challenge posed to our health by chemical poisoning. A cursory observation of our health care system in Nigeria on the state of quality of care and disparities in care shows that, the gap between the best possible care and that which is routinely delivered remains substantial. This if not addressed will further exacerbate the chemical poisoning situation that may worsen with economic refoms focusing on mining and increased geological activities. The following are therefore specifically recommended: The nation's biomedical laboratories must be equipped to ensure easy and early diagnosis of chemical poisoning or c hemicall y-induced diseases. All known mining areas should be linked to centres providing toxicological investigations for surveillance- probably under the umbrella of a National Institute of Environmental Health Sciences W H S ) (Regional Toxicology Laboratory). There is need for a national survey of the major toxic substances preferably combined with nutritional assessment. There is the need to establish an agency to study various aspects of the toxic effects of chemicals in Nigeria, comparable to the Agency for Toxic Substances and Disease Registry (ATSDR) in the United States. Provision of facilities and strengthening of laboratories in at least some designated Uni versi tiemesearch Institutes to study the silent epidemic of chemical poisoning is currently a priority. Introduction of courses of instruction in toxicology in schools, including undergraduate and postgraduate courses in the universities and establishment of a standing committee to disseminate information through public enlightenment programmes in collaboration UNIVERSITY OF IBADAN LIBRARY with the Federal Ministry of Information and Culture, emphasizing the adverse effects of toxicants or chemicals are desirable strategies. Owing to the special sensitivity of children, Children Survey/Study is needed, possibly under the auspices of Children's National Environmental Toxicology and Micronutrient Programme (CNETMP). This may progress to the establishment of a Children's National Toxicology and Micronutrient Centre. Finally, other sources of poisoning to the general population, such as use of pesticides to preserve grains, vegetables and peas, food additives, drugs, chemicals in automobile and home paints, etc should also be addressed. The Proposed Toxicology Research Laboratory (TRL) in Chemical Pathology This brings me to the proposed Toxicology Research Laboratory (TRL), a clinically biased toxicology laboratory in the Department of Chemical Pathology. I thank the immediate past Vice-Chancellor, Professor LF. Adewole, FAS, for being the arrow head of this project. I will seize this opportunity to give a situation report. Before the last administration left office, the proposal was approved by the Senate of this university and awaiting funding, which I am sure our dear Vice-Chancellor will quicken fund release. I am happy to report that as part of the .process of implementing. the TRL proposal, I successfully coordinated the k t comprehensive training in Basic & Clinical Toxicology (BCT) attracting over 60 participants drawn from many parts of the country (fig. 23). Activities like this and many others are wHat the TRL plans to be involved in. One of our books (fig. 24) is an example of the type of monographs TRL plans to publish periodically to compressively address the problem of chemical poisoning in Nigeria. UNIVERSITY OF IBADAN LIBRARY F& 23= Progmme far the fwst basic and clinical toxicology callr~ei n hI mivdty. UNIVERSITY OF IBADAN LIBRARY FEg. 24: A book co-authod by the lectllra: the TRL plans to prod- monographs in clinical toxicology. A book like this would have been very handy in W a n tS tate. 4 Acknowledgeme~~ts i . First and funmost I give all the thanks, gory, honour, praik and adoration to God, who has made everything possible. G l m i n Excelsis Deo. I thank my parents, particularly my mother for all the sacrifice for my education and especially fur buying the first books that opened the doors of science to me, Introduction to Chemistry and Physics by Philip and Dotun Oyewole. I also thank a l l my mateanal uncles (the Eimunjezes) - and their wives, particularly, Mr. Henry UNIVERSITY OF IBADAN LIBRARY Eirnunjeze, Mr. Victor Eimunjeze, Mr. Dickson Eimunjeze and Mr. Patrick Eimunjeze for their support to my mother in my upbringing and education. I thank immensely the Doctors and Rev. Sisters at St. Camillus Catholic Hospital, Urorni, whom I was told were wonderful when I took seriously ill. I would not have been here today. In the words of Nolan Ryan: " I am going to spend my time today, just thanking the people that played a role in my career, because I truly do believe that I was blessed by a lot of people whose path crossed mine as I went down the road of my career". My deep gratitude goes to my academic mentors beginning with Professor Francis Adefikayo Adebayo Adeniyi, who supervised both my fellowship thesis and was the chief supervisor of my PhD thesis. He was the one who introduced me to research. I thank him for his care, love, inspiration, counsel, guidance, encouragement, and above all prayers. My special gratitude goes to Professor Grace Oladuni Olaniyan-Taylor. FAS, she was a member of the panel that interviewed me for admission into the Medical Labomtory Science Programme in 1976, supervised my ' M . k dissertation in chemical pathology and a co-supervisor 'of niy PhD thesis (Ish ifted from lipids to toxicology). She is more like a mother to me and the entire family, her thoroughness, genuine mentorship up till now is greatly appreciated. I thank my PhD External examiner, Professor Umoh, who in addition to examining me counseled me to change from a service career in DCTA to the university system and told my department to give me a position. I am indebted to Professor Nurudeen Adedipe for nominating me for the Scientific Committee on Problem of the Envirmment (SCOPE)/IUPAC International Symposium on Enc Dcrine Active Substances (EACs), Yokohama, Japan. I thank Professor M.&C. Sridhar my Internal Examiner for the PhD and for recommending me to be a member of the National Committee on the removal of lead from Nigeria' s gasoline and his letter of support to the United Nations Scientific Committee on problems of the Environment (SCOPE)/ UNIVERSITY OF IBADAN LIBRARY IUPAC to attend the symposium on Endocrine Active Substances in Yokohama, Japan. I owe a lot of gratitude to all my teachers at the School of Medical Laboratory Sciences, Uni versi ty College Hospital, Ibadan, a school that even though unsung has produced well over forty professors and PhDs combined, not counting MSc and Fellowship holders. I cannot but mention, late Mr. F.A. Lukanmbi, M.Phil., FIBMS (UK), a real master of chemical pathology and mentor, Mr. E.A.B. Mould, MSc. FIBMS (UK), a great teacher of chemical pathology, motivator and friend, Professor Theo Olawoye, Professor Ernest Ukaejiofor, Late Professor R.A. Alegbe, a great teacher, Mr. P.F. Idowu, late Mr. J.E.O. Durowoju, Mr. Dennis Opene, Mr. Bayo Lawal and several others. The sound foundation and exposure you laid will forever be cherished. I thank late Mr. Daniels, FRCS (Lond.), formerly of ENT Department, U.C.H., he housed me, cooked for me and guided me in my final year in UCH. May your great soul rest in perfect peace. I also thank my first employer in my career, Dr. Benjamin h i Okpako, a surgeon and great administrator, former Medical Director of Benoni Hospital, Benin City, for your love and belief in me and for making me the Secretary to the Clinical Committee of the hospital inspite of clandestine opposition. I thank my bosses in IITA, Dr. Olufemi Ogundipe for the facilities you put at my disposal and opening your home to me and my family at all times, Dr. Funmi Ajose, for your understanding and support, Mr. Thackway, Head of Human Resources for your interest and your initiation and approval of my training in Scotland. I also appreciate Dr. and Mrs. Joe . Mullongoy for their friendship and love throughout our stay in IITA. I thank the management of Igbinedion University, Okada for giving an opportunity for Sabbatical leave between 2008 and 2010. I must thank the following Dr. J.F. Pleysier, Mr. Joe Uponi of the Analytical Service Laboratory (ASL) lITA and Mr. William Ebadan Formerly of the ASL for their considerable technical assistance. Thank you indeed. I will always remember, my former landlord, late Mr. Dapo Aloba, UNIVERSITY OF IBADAN LIBRARY FCA, a truly detribalized Nigerian who was more like an uncle or father. May your great soul rest in perfect peace. I bountifully acknowledge all my international teachers, mentors, and c o l l ~ t o r sa s follow: Dr. Ian GouId, FRCPath, Department of Medical Microbiology, Division of Labratory medicine, University of Aberdeen, Aberdeen Royal I n f w (A RI), Scotland, Dr. Ian Ross, fonner Head, Department of Clinical Biochemistry, University of Aberdeen M d c d School, late Dr. Neil Patemon, Ph.D, Chief of Toxicology and Deputy Head, Department of Clinical Biochemistry, University of Aberdeen, Dr. Arthur Dickie, Professor John Broom, Dr. Ian J. Rothnie, Dr. Anthony Seaton, Department of Environmental Health, and Drs John Cheskrs and John Arthur, Trace Element and Gene Expression Laboratory, Rowett Research Institute (RRI), Bucksburn, Aberdeen. I thank in a special way professor Shoji Fukushima, MD, Ph.D, Pathology Department, Osaka City University Medical School, Osaka City University, Osaka, Japan. I thank others in this Laboratory, Professor Hideki Wanibuchi, Dr. Anna Kinoshita, Dr. Min Wei, Dr. Kunichiro h i , P rofessor Salim, Ms. Tuoma, Ms Mari Doko, Dr Akira Inoue and Dr. Kang. Late Dr. Junshi Miyamoto, SCOPE LOC Chairman Yokohama, Japan 2002, and former Head, Chemical Evaluation Research Institute (CERI) , Tokyo, Japan; Dr. Mark D. Evans, Department of Cancer Studies and Molecular Medicine, University of Leicester ; Professor Peter Farmer, Biomarker Laboratory, University of Leicester, U.K., and Professor Marcus Cooke, Department of Environmental and Public Health, Florida International University, Florida. Professor Robert Flanaga n, Toxicology Unit, king' s College Hospital, London, Dr. Andrew Taylor and Dr. Chris Harington, Trace Element and Toxicology Laboratory, Sanger Research Park, University of Surrey . Professor Anthony Okorodudu, Clinical Chemistry Division, Department of Pathology, University of Texas Medical Branch, Galveston, Houston, Texas, Professor Jonna ~honkasR, MIT University, Bundora, West Australia, Anita UNIVERSITY OF IBADAN L BRARY Mietttunen, Environment Canada, Dr. Mary J. Brown, Chief LRad Poisoning Prevention Branch, C X ,A tlanta, Georgia. I wish to acknowledge with gratitude the Funding support of 'the under listed organizations; Aberdeen Rotary International, Scotland, International Institute of Tropical Agriculture W A ) , Lijima Foundation, Japan, Osaka City Medical School and Medical Centre, Osaka, Japan, C. P. Stewart Memorial Fund, ACB, UK, Royal Society of Chemistry, U.K., IUTOX/SOT,-U niversity College Hospital (UCH), the University Ibadan and TETFUND. I thank all my teachers in the Department of Chemical Pathology; I cannot but Mention Professor Bola Osifo for rekindling my interest in Intermediary Metabolism and Professor Abayomi Akanji, FACB, FAS, a true scholar and believer in meritocracy. I am especially grateful to Professor Emmanuel 0.A gbedana the only one left among my teachers in the department; I call him 'the last of the Romans,' for helping to hold the department together, for being the link between the past and present and for his myriad advice and counsel. I thank the cumnt Head of Chemical Pathology Department, Professor Ganiyu Olatunbosun Arinola. I thank the following: Professor Babattmcle Osotimehin, FAS, one of those who interviewed me for the Job, Iate Professor Lekm Salimonu, FAS, the Head of Department when I was employed, late Professor Christopher Adesuyi Adejuwon, a great teacher and believer in me, late Professor A.I.0. Williams. I thank all my cunent colleagues for their comradeship, Dr. K.S. Akinlade, Dr. F.M. Abbiyesuku, Dr. K.S. Adedapo, Dr. O.M. Akinosun, Dr. Mabel A. Charles-Davies, Dr. LO. Omotosho, Dr. M. Kuti, Dr. A.A. Onifade, Dr. Elizabeth Bolajoko, Dr. Dr. Enitiame Orimadegun, Mrs. Ademola-Aremu. I thank all the non- teaching staff in the department, Mrs. Adeyerno, Mrs. Taiwo, Mrs. A h t i , Mr. Titiloye, Mr. Taiwo and the indefatigable ever smiling, ever helpful, Mr. Dele Ayede. I thank the administrator and secretary of the Department of Biomedical Laboratory Science for the support in running the department. UNIVERSITY OF IBADAN LIBRARY I thank all the members of the Faculty of Basic Medical Sciences for miscellaneous assistance at one point or the other. I am very appreciative of the various assistance of the cumnt Faculty Officer, Mr. Akande. I appreciate all staff of the College of Medicine especially, Professor Babatunde Lawal Salako, the immediate past Provost. I wish him well in his new assignment. He will be sorely missed. I thank Professor Oladipo 0.A kinkugbe who though did not teach me directly, I have learnt a lot from his words of wisdom and specially for involving me in the Olusegun Obasanjo Presidential Library and Centre for Human Security book project on the Health Sector. I also thank the late professor A. Adetuyibi for his prediction about me and particularly for his book, 'An Introduction to Biomedical Research for Health Workers in the Tropics'. It was very useful in my formative years. I appreciate the friendship and love of the following Professors-4.0. Olorunsogo, E.O. Farombi, O.G. Ademowo, O.D. Olaleye, E.E.U. Akang, (Late), A.R.A. Alada, S.B. Olaleye, Georgina Odaibo Drs. T.S. Akingbola, F.A. Fashola, Dr. Solomon Adeleye Bakarey, and many others too numerous to mention here. I thank the Deputy Provost Professor Ademola Ajuwon, Director of IAMRAT ~rdfessorC atherine Falade and the College Seretary Mrs. Olubunmin Faluyi. I thank in a special way the following; Professor 0.0. Osibanjo, Professor Sunday Ajayi; great teachers of analytical chemistry, Professor Temitope Alonge Chief Medical Director UCH, A/Level course mate and boyhood friend, for the long-term aspiration and dream we shared about science and scholarship, late Professor Theophilus Akinleyeie, Professor Mba Ogburuigwe OkomIlkwo, OON, National Open University of Nigeria, for his encouragement and brotherly love, Mr. Tunde Anifowoshe, a friend of over forty years, whose contribution to today's event is immeasurable, Professor Anthony Emeribe, Professor, A.A . A1 aribe, Dr. Layi Oduwole, A yo Norman-Willi ams, Air Cornodor (Dr.) UNIVERSITY OF IBADAN LIBRARY Yomi Alunwale, Dr. Godswill Okara, classmates and friends and many others, Professor Adolphus Uduh, All members of Forum of lbadan Toxicologists (FIB ATOX), especial1y Dm. Ademola Oyagbemi and Adeolu Adedapo, All members of the management Committee of the Multidisciplinary Central Research Laboratory (MCRL) chaired by Professor Bankole Oke. I thank all my past and present postgraduate students, I cannot but single out Chukwuemelie Zedech Uche for his 'sonly' attachment and assistance, and for the dream we share. I also thank Mr. Eden for all his technical assistance. I openly confess that I have also learnt from you. I wish to thank Professor Sylvester Osegele Ori aifo, the first Professor in our family to whom I have been attached since my secondary school days for all his care, guidance , admonition and prayers. He was the guardian angel God used to bring me to Government College, Ughelli, the school originally .chosen for me by my head master but turned down by my uncle for good reasons. I also thank his wife, Mrs Clara Oriaifo, who is more like a senior sister. I thank Dr. Adolphus Oriaifo, MD, PN), FMCS, for all his care. Thank you specially for being there as the doctor of the whole family that gave me peace of mind to face my academic pursuit. It was actually you who first described medical research in my presence when you were describing your Ph.D work on your return, how you broke the legs of chickens; you were applying something and watching the response; the legs healing and straightening. Unknown to me I would decades later find myself in your shoes. I must thank my late grandmother, Madam Egbakhuangie Eimunjeze for all her sacrifice; it pains me that you did not live to gain anything from me. I also thank all my mother's sisters (my aunts), particularly Madam Monica Ibhahiobheson Eimujeze, who stepped in as the mother of the Eimunjezes when my grandmother passed on. I also thank my mother's younger sister, Madam Beatrice Atuoriakhi Oriaifo, who took special interest in me. I recall your concern that UNIVERSITY OF IBADAN LIBRARY p p l e w ere saying they didn't d l y u nderstand what I was studying. I assured you that it was a good field; wished you were here today. I thank Mrs. Atuegbe Eiwone, the last of my cherished aunts to depart. All your prayers were certainly heard by God. Rest in peace. My thanks go to all the other Oriaifos; Aunty Stella, Mrs. Ogbebor (especially for accepting her colleagues' suggestion that I repeat primary three), I thank Chief (Mrs.) Victoria Akhere Aaadlm (ourmummy in badan) and the late husband, Chief Ayo Adedun, her twin, Dr. Victor 0.O riaifo all their help when I was studying and now as well. I thank aunty Felicia, P h m . (Mrs.) F.E. Odaro, FPSN. I thank Professor (Mrs.) Justina Aire and the husband, Professor Tom. A. Are. The succor you gave to me and my friends, will never be forgotten. I thank all my siblings and cousins of my age group, Iwobhor Godwin Anetor, Paul Anetor, Mrs. Bennie Anetor, Beatrice Adesua Eimunjeze, Mr. Alexander Oriaifo (kxy) , Bamster Otunba Fi&lis Oriaifo (F~do),R ose Eimunjeze, Mrs. Ornoso Matankari. I remember in a special way late Banister Felicia Omonigho Eimunjeze (former Deputy Director of the Law School, Yenagoa, Bayelsa State) who was tragically killed on the 13& of February this year by a careless truck driver. I also appreciate all my younger cousins, too numerous to mention here individually. I am grateful to you all. I thank specially Dr. and Mrs. Andrew Bella and Professor and Mrs. Peter Aziba as well as late Mr. Shola Bademosi, AIMLS, a classmate and true compatriot, may your soul rest in peace. I wish to thank dl the priests, religious and members of the various pious societies of the Catholic Church, too numerous to list individually I have k e n associated with all over the world. I cannot but mention The former Metropolitan of the Catholic Arch Diocese of Ibadan, Arch Bishop Alaba Job and his successor Arch Bishop Gabriel Abegurin, members of the Opus Dei Family, Sisters of the Mary Hill UNIVERSITY OF IBADAN LIBRARY Convent. Ibadan, parishioners of Seat of Wisdom Chaplaincy, U.L, St. Luke Chaplaincy, UCH, Holy Family, Akobo, St. Anthony's Catholic Church, Uromi, The Catholic Cathedral, Bauchi, St. Mary's Cathedral, Huntley Road Aberdeen, St. Joseph Osaka and many more. The Catholic Church has been a home where ever I went. Thank you all. I thank the youngest of my uncles specially, Mr. Vincent E. Eimunjeze and his wife Mrs. Janet (mama Boje) Eimunjeze for he it was who brought me to Ibadan to receive education. I wish to thank my in-laws for their love care and generosity; Late Mr. Caxston Ainoje' and Mrs. Grace Iyoha Azenabor, Mrs. Clara Azenabor-Awonuga, Mrs. Marie Stella Odanmen, Professor Antony Azenabor, Professor Godwin Azenabor and all others too numerous to list here. I will forever cherish the daughter you gave me. I thank my jewel of inestimable value, h. Oloria Oiyahumen Anetor, a sweet heart and better half indeed, who has toiled with, supported me and sacrificed for me. You have given your all. I will never forget the sacrifice of your shouldering the responsibility of both of us and two children alone when Iwent on study leave without pay for the M.Sc. programme without our two families knowing it. I do not have the adjective to express the depth of my gratitude to you. All I can say is thank you, thank you and thank you. May God bless you richly. You and the children are the sunshine of my life. I thank the children, B m . Oseiwe Joan Anetor, Dr. Ehimudiamen Anne Anetor, Dr. Oselumense -John Anetor, Mr. Benosehoole Edward Gerald Anetor my nephew, Mr. Eromosele Joshua Anetor, and a close friend of the children who is like a son to me, Eng. Samuel Ailenubhi for their love and understanding. I love you all. This lecture is dedicated to Our Lady, the Blessed Virgin Mary and late mother, Madam Magdalene Omobhakhamen A,n ..-eI tor (Nee EimunjezeI ).. . , ,:,Thanky ou all for listening. . . a UNIVERSITY OF IBADAN LIBRARY References Adeniyi, F.A.A. and Anetor, J.I. (1999) Lead poisoning in two distant states of Nigeria: An indication of the Real size of the problem. Afr. J. of Med. and Med. Sc. 28: 107-1 12. Adeniyi, N.A., Omotosho, I.O., Onifade, A.A. and Anetor, J.I. (2016) An Assessment of the modulatory effect of zinc on humoral immune parameters in welders and cement block moulders in Ogbomos ho, Nigeria. JIRESH- Biotech (in press). Agbedana, E.O. and Anetor, LI. (2006) Urinalysis in clinical and laboratory medicine. John Archer Publishers: Ibadan. Akingunola, R.O. (20 11 ) Small and medium scale enterprises and economic growth in Nigeria: An assessment of financing options. Pakistan Joumd of Business and Economic Review 2: (I). Alsberg, C.I. and Schwartze, E.W. (1919) Pharmacological actions of cadmium, J. Phamcol . 13: 504-505. Anetor, J.Z. (1997) An Evaluation of the Nutritional, Metabolic and Immune Status in Occupational Lead Toxicity. PhD Thesis, University of Ibadan. (200 1b ) High blood lead levels in the general Nigerian Population: Causes and implications The World Bank Working Paper No. 6: Clean Air initiatives in Sub-Saharan cities in Africa. National Conference on the phase-out of lead. World Bank, Washington DC 20344, pp 27-37. (20 12 ) Rising cadmium levels in developing countries: Threat to genome stability and health. Nig. J. Physiol. Sci. 27: 103-11 5. 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UNIVERSITY OF IBADAN LIBRARY BIODATA OF PROFESSOR JOHN IBHAGBEMIEN =TOR John Ibhagbemien Anetor was born on Sunday about midday of May first (May Day) 1955 at St. Camillus Catholic Hospital, Uromi, Edo State to Mr. Aimakhu Ogudo and Mrs. Magdalene Omobhakhamen Anetor (Nee Eimunjeze). The father was a forester, palm produce merchant and a community leader, while the mother was a rice and fish merchant at the famous flushi (Ozigono) market, located on the bank of the River Niger. H e started his primary education at the Local Authority (L.A.) School at Utah, Urumi in 1963, he could not start earlier as his hand could not cross his head to touch the ear on the opposite side. He transferred to St. Anthony's Catholic Primary School, Okpujie, Uromi in primary three, where he spent two years in primary three, 1965 and 1966. H e finished his primary education in December 1969. It is remarkable that many of his school mates rarely called him by his name, instead he was known and called 'Ebo' (White man; due his fair complexion) even up to the first two years in secondary school. John Anetor started his secondary education at khan Grammar School (IGS) in January, 1970, and transferred to Government College, Ughelli (GCU) in form three (The school his headmaster chose for him Erom the beginning but turned down by his uncle) and obtained the West African School Certificate (WASC) in June 1974. Chemistry was his best subject in which he obtained a distinction. He started his Advanced Level (An)c ourse in science (Physics, Chemistry & Biology) at the Faculty of Science, University of Ibadan, under the Extra Mural Programme of the Faculty of Education in the 1975f76 session. He left after one year of the two-year programme to study Medical Laboratory Science at the University college Hospital (U.C.H.), in the 1976/77 (started January 1977) and qualified in June 1981 obtaining the Associate Membership of the Institute of Medical Laboratory Science of Nigeria (AIMLS) with option in chemical pathology. He was adjudged the overall best graduating student winning the then Professor UNIVERSITY OF IBADAN LIBRARY Kolawole's Prize for the Best Academic Student. He served the mandatory National Youth Service in Bauchi State, with his primary assignment at the General Hospital, Darazo, completing the service in July 1982. There after he took up employment in the Pathology Department as Medical Laboratory Scientist at Benoni Hospital Limited, Benin City on August 2"d 1982 and left to join the Medical Centre of the International Institute of Tropical Agriculture (IITA), November 28 1984, where he rose through the ranks to become a Manager. He got married on August 3lSt1 985 to Miss Gloria Oiyahumen Azenabor (now Dr. Gloria Anetor) the younger sister of his friend and colleague, Tony Azenabor, now a Professor of Immunochemistty at the University of Wisconsin, Madison, United States of America. John registered for the fellow ship programme (professional postgraduate course) by thesis in chemical pathology in 1987 and successfully defended his thesis in 1989 and was awarded the specialist fellowship of the IMLS (FIMLS) in chemical pathology. He was admitted to study for the academic master's programme (M.Sc.) in the Department of Chemical Pathology, College of Medicine, of the University of Ibadan in the 1990/91 session. John graduated as the best student in his set and the only one who obtained the PhD grade. He registered for the doctoral programme in chemical pathology in January, 1992 and successfully defended his PhD thesis in April, 1997. He had predoctoral attachment with the aid of the Aberdeen Rotary International Fellowship at the Laboratory Medicine Division of the University of Aberdeen Medical SchooYAberdeen Royal Infirmary (ARI),S cotland in 1995, with visits to the Rowett Research Institute (RRI), Buc ksburn, Aberdeen after earlier training in Clinical Laboratory Medicine at the City Hospital, A b e d z n and the Aberdeen Royal Infirmary in 1990. Dr. John Anetor had his postdoctoral training in the Pathology Department at the Osaka City University Medical School, Osaka City University, Osaka, Japan, under the supervision of Professor Shoji Fukushima, MD, PhD. in 2005. He worked on chemical carcinogenesis and chemo- prevention. He joined the services of the University of Ibadan UNIVERSITY OF IBADAN LIBRARY from IITA, Tbadan, 15" December, 1998 as Lecture II. He was promoted Lecturer I on October 1, 2001, Senior Lecturer in 2004 and got his Chair in chemical pathology on October 1, 2010. Before this he was appointed a Professor of Chemical Pathology at the School of Clinical Medicine at Igbinedion University, Okada while on Sabbatical leave between 2008 and 2010. They infact argue that they were the first to pronounce him Professor. He was appointed a Consultant Chemical Pathologist to the University College Hospital WCH) Ibadan, in 2006 and later designated Specialist Adviser in Chemical Pathology in 201 1 to date. He has sewed as a consultant to the Medical Centre, International Institute of Tropical Agriculture on many occasions. He is an Adjunct Professor in the Department of Chemical Pathology and Immunology, Olabisi Onabanjo University , Ago-Iwo ye, Ogun State. He has been external examiner at both undergraduate and postgraduate levds in almost all the major universities in Nigeria and a West African country. Professor John Anetor was a visiting scientist at the Department of Cancer Studies and Molecular Medicine, University of Leicester, U.K. in 201 1. He visited the Department of Pathology (Clinical Chemistry Division), University of Texas Medical Branch, Galveston, Texas in 2012. 'In 2014 he was awarded the C. P. Stewart Memorial Fund of the Association of Clinical Biochemistry and Laboratory Medicine (ACB), U.K to train in Analytical Toxicology at the Toxicology Unit, Department of Clinical - Biochemistry, King's College Hospital, London, with attachments at the Bioanalytics and Toxicology Unit (ASI), Pharmacology Department, St . Oeorges University, London and the Toxicology and Trace Element Laboratory (Supra- regional Assay Services, SAS) at the University of Surrey, Guildford, Surrey. John Anetor has enjoyed many travel grantslfellowships. He was awarded the UNESCOAUPAC fellowship in 2002 to attend the International Workshop on Endocrine Disrupting Chemicals WCs) in Yokohama, Japan. He won the Gordon Research Conferences (on Genetic Toxicology) Fellowship twice, 2007 and 2008, got the national Universities Commission (NUC) travel grant in UNIVERSITY OF IBADAN LIBRARY 2009, the International Union of Toxicology (IUTOX)/the Society of Toxicology (SOT)t ravelling fellowship in 2013. John Anetor is a member of many professional and learned societies locally and internationally. He is a Member, Association of Clinical Chemistry of Nigeria (ACCN), where he was a Treasurer. He is registered with the Medical Laboratory Science Council of Nigeria (MLSCN). He is a Fellow of the Institute of Biomedical Science (FIBMS) of the United Kingdom (UK), Member, Association Clinical Biochemistry and Laboratory Medicine (Am) of the United Kingdom. He represents Africa on the Committee on Traceability in Laboratory Medicine (C-TLM) of the Scientific Division (SD) of the International Federation of Clinical Chemistry and Laboratory Medicine (FCC).H e is a Member, Society of Toxicology (SOT)o f the United States of America He is a founding member and Adviser to the West African Society of Toxicology (WASOT). He is a Fellow of the Royal Society of Chemistry (FRSC) of the United Kingdom. He is a Fellow of the American College of Nutrition (FACN), he is a European Registered Toxicologist (ERT), a Life member of the Environmental mutagen Society of India (EMSI) and an honorary Fellow, Institute of Industrial Administrators of Nigeria )He .has p ublished extensively, one hundred and eight papers (108) at the last count, (not- counting published abstracts) including several book chapters and a co-authored book, 'Urinalysis in Clinical and Laboratory Medicine'. He has supervised and co- supe~sed1 0 PN) candidates many of whom are occupying senior positions with one in the professorial cadre, 20 MSc candidates and 4 Fellows hip candidates. He is a reviewer for many national and international p r reviewed journals and sits on several editorial boards. He is the pioneer editor of the African Journal of Laboratory Medicine and Biomedical Research, based in the Southern Africa Training Academy (SATA) located in South Africa. Professor Anetor has served the university, the University College Hospital (UCH) and the nation in many capacities. He is the Vice-chairman of the University College Hospital Research Committee. He was a member of the National UNIVERSITY OF IBADAN LIBRARY Committee on the removal of lead from Nigeria's gasoline, sponsored by Exxon Mobile and the World Bank. His psentation at the conference is incorporated into the Working Paper No. 6 on the Clean Air Initiative in Sub- Saharan Africa. He was in late 2015, invited to be a member of the team of reviewers of the Olesegun Obasanjo Presidential Library book project, 'Towards a New Dawn for the Health Sector in Nigeria Post 2015' by the coordinator, Professor 0.0.A kinkugbe, FAS. John Anetor is an active participant in the Faculty of Basic Medical Sciences, where he is a memlxr of the central committee of the Unibadan Conference of Biomedical Research (UCBR), and was the Chairman of the Scientific Sub-Committee of the 2016, UCBR biennial conference, he is a member of the University of badan Senate Curriculum Committee, a member of the management committee of the Mu1 tidisciplinary Central Research Laboratory (MCRL). He is the Chair of the Forum of Ibadan Toxicologists (FIBATOX). He was a former coordinator of postgraduate programme in the department of chemical pathology; and the current chairman of the departmental postgraduate committee of the Department of Chemical Pathology. He is also the Coordinator of the Nutrition and Metabolic module of the departmental postgraduate courses. He is the Head of the Toxicology and Micronutrient Metabolism Unit of the department and coordinated the first certificate course on Basic and Clinical Toxicology (BCT) attracting participants from all over the country organized by the Department of chemical pathology. Professor Anetor is the current head of the Department of Biomedical Laboratory Science, Faculty of basic Medical Sciences, College of Medicine, of this university. John Anetur is a confirmed and committed Catholic. He is married to Dr. Gloria Anetor, a Senior lecturer and Ag. Head of the Department of PublidEn vironmen tal Health of the National Open University of Nigeria (NOUN), Lagos and the union is blessed with four children, UNIVERSITY OF IBADAN LIBRARY NATIONAL ANTHEM Arise, 0 compatriots Nigeria's call obey To serve our fatherland With love and strength and faith The labour of our heroes' past Shall never be in vain To serve with heart and might ' One nation bound in freedom Peace and unity 0 God of creation Direct our noble cause Guide thou our leaders right Help our youths the truth to know In love and honesty to grow And living just and true Great lofty heights attain To build a nation where peace And justice shall reign UNIVERSITY OF IBADAN ANTHEM Unibadan, Fountainhead - Of true learning, deep and sound Soothing spring for all who thirst Bounds of knowledge to advance Pledge to serve our cherished goals! Self-reliance, unity That our nation may with pride Help to build a world that is truly free Uni€l&m, first ;and best Raise true minds fm a noble muse Social justice, equal chance Greamss won with honest tail Guide our people this to know Wisdom's best to m i c e turned He$ enshrine the right to learn For a mind t h h a w s is a mind that's free UNIVERSITY OF IBADAN LIBRARY UNIVERSITY OF IBADAN LIBRARY