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This paper assesses the capacity of animal models to predict human response to carcinogenic agents with consideration for the heterogeneity of humans. It is widely accepted that human susceptibility to toxic substances, including carcinogens, is highly variable. Conventional rodent models are usually highly inbred and valued for their ability to display characteristic homogeneity. Current practice assumes that the homogeneity of response to toxic agents, including carcinogens, in the rodent model will be representative of humans. The issue then becomes, To which of the broad spectrum of human responses are specific animal models likely to be related? This paper examines the extent of human heterogeneity over a broad range of biochemical characteristics (e.g., aryl hydrocarbon hydroxylase activity, epoxide hydrase activity, beta-glucuronidase activity, debrisoquine hydroxylation, DNA-adduct formation) with emphasis on those biochemical characteristics that affect responses to carcinogens. Examples are presented to compare the heterogeneity of selected animal models for these biochemical characteristics as they relate to the spectrum of human responses noted above. The paper presents a theoretical perspective for determining to which part of the human population response spectrum common animal models are most likely to be extrapolated.

Individuals with the genetically inherited condition of latent porphyria have been previously hypothesized (1) as being a potential high risk group to elevated lead exposure. More specifically, persons with either clinical symptoms of porphyria or the latent form who also are exposed to excessive lead may have their clinical symptoms exacerbated or possibly induced prematurely, respectively. This paper presents evidence that an animal model (i.e., domestic cats with congenital porphyria) may facilitate the testing of the previous hypothesis.

Using ascorbic acid as a model, this paper proposes that the concept of the RDA should be broadened to take into account the effects of ubiquitous pollutants on human health, a factor presently not incorporated in RDA derivations. It is now widely accepted that ascorbic acid nutritional status markedly affects the toxicity and/or carcinogenicity of greater than 50 pollutants, many of which are ubiquitous in the air, water, and food environments. At the present time, the data do not warrant changing the ascorbic acid RDA in light of the knowledge of pollutant interactions.

Four cases are presented which suggest that the present U.S.E.P.A. drinking water standard for selenium of 10 micrograms/L in inappropriate. The rationale upon which this standard is based is that selenium is carcinogenic, induces dental caries formation, and is highly toxic to animals. However, a critical assessment of this literature can not support these claims. Case no. 1 demonstrates that there is insufficient evidence to classify selenium as a carcinogen. Data derived from the three respective groups of researchers claiming a carcinogenic effect induced by selenium are obscure due to 1) the inability to accurately identify malignancies, 2) the apparent opposite effects of different selenium compounds, and 3) the lack of proper controls. Case no. 2 reviews recent evidence that selenium reduces the incidence of cancer in laboratory animals and in man, an effect which can probably be attributed to the antioxidant properties of selenium compounds. Case no. 3 provides evidence which does not permit the classification of selenium as a cariogenic element. Epidemiological studies supporting such a claim are inadequate since they lack properly matched control groups. Animal data do not support this link as well. Case no. 4 is a review of studies which clearly demonstrate the essentiality of selenium, an aspect of selenium metabolism that was not considered when the 10 micrograms/L standard was promulgated. In light of the four cases presented and an assessment of selenium toxicity in man, it is concluded that the 10 micrograms/L standard can not be justified. Instead, it is suggested that 50 micrograms/L selenium should provide sufficient protection from the toxic effects of this element. This is consistent with the current state of knowledge with respect to the potential adverse health effects associated with selenium.

Consumption of a specific oral contraceptive (OC) preparation resulted in the enhanced gastrointestinal (GI) tract absorption of calcium. Since calcium and lead may compete for the same binding site in the GI mucosa and since lactose enhances the GI uptake of a variety of minerals such as calcium and lead, it is speculated that other agents such as certain OC preparations which facilitate the GI absorption of calcium may also enhance the GI uptake of lead.

The dominant role of the physical and chemical environment in the development of cancer is challenged. Analyses of the etiology of skin, bladder, respiratory and gastric cancers are presented which demonstrate the considerable extent to which one's health status may modify the initiation and promotion of environmentally associated cancers. It is concluded that although environmental factors may initiate and/or promote 85 to 90 percent of all cancers this is misleading since it neglects the critical role of the individual's health status as a factor modifying carcinogenesis.

Chlorite, a by-product of chlorine dioxide disinfection of water, is a strong oxidant compound that produces markedly exaggerated effects in vitro on red cells of G6PD deficient humans when compared to normal human cells. Levels of methemoglobin are significantly greater and GSH levels significantly lower in the G6PD deficient cells than in normal cells after chlorite exposure. Persons with G6PD deficiency may be 3 to 4 times more likely to develop hemolytic anemia from chlorite exposure as persons with normal activity levels when GSH levels are used as a measure of susceptibility. The proposed use of chlorine dioxide as an alternate disinfectant for drinking water supplies should consider this potential high risk group.

Because chlorination of potable surface waters may be associated with increased risk of carcinogenicity, substitute methods for the routine disinfection of public water supplies are being explored. As part of this search, it is especially important that the potential health effects of each alternative method should be considered. Chemical treatment of drinking water by chlorine dioxide (ClO2) is a likely alternative mode of disinfection. Two common by-products of the ClO2 disinfection of surface water are chlorate and chlorite. These oxidants may have negative health effects on certain high risk groups. Newborns, in particular, would seem to be at increased risk to red cell damage from oxidant stress. The historical record study being reported here compares the morbidity and mortality experience of newborns in two similar communities, one of which used chlorination and the other which used high levels of chlorine dioxide for potable water disinfection. A statistically significant positive association was found between exposure of the mother to ClO2-treated water during pregnancy and prematurity of the newborn as assessed by the attending physician and by a greater weight loss after birth. The rates of jaundice, birth defects and fetal and neonatal mortality did not differ significantly between communities. Because of the limitations of the study design, the findings reported here should be considered suggestive rather than definitive.

It has been proposed that elevated concentrations of homocystine in vascular tissue could cause arterial damage leading to arteriosclerosis. This theory is indirectly supported by research in the area of environmental toxicology, which has revealed that carbon monoxide and carbon disulfide, agents whose prolonged exposure is known to result in the development of arteriosclerotic changes, induced vitamin B6 deficiency states which predictably lead to a homocystinuria-like state. Such information provides strong indirect support of the controversial homocystine theory of arteriosclerosis.

The use of evolutionary theory to understand and predict environmental quality indices has been described. Three specific examples concerning the environmental health implications of black skin, heat stress adaptation, and G-6-PD deficiency have been discussed in which evolutionary theory provides the conceptual framework for novel insights and reasonable predictions of environment, pollutant and human interactions. The use of the evolutionary paradigm in the development of environmental quality indices offers a clear alternative to trial and error research efforts.

The development of Inspection and Maintenance Programs to control automobile emissions are one component of a comprehensive strategy to reduce automobile related air pollutants such as CO, NOX, and HC. Since the efficiency at which most motored vehicles are designed to limit pollutant emissions deteriorate with prolonged driving, an Inspection and Maintenance system is needed to restore the ability of the automobile to achieve its designed emission standards. Several types of approaches toward developing Inspection and Maintenance Programs in the U.S. including city, county, and state levels of organization and their effectiveness have been described. However, information on the efficiency of these approaches in achieving reductions in pollutant levels remain to be documented, as well as the cost effectiveness of such programs, and their acceptance by the public. In light of the important role that Inspection and Maintenance Programs have been projected to have in the U.S. in reducing automobile related air pollution, it is recommended that interdisciplinary research projects evaluating the multiple dimensions of Inspection and Maintenance Programs be initiated.

Catalase activity is found primarily in peroxisomes although in some species and in some organ systems, cytosolic catalase also may be involved in intracellular oxidant stress protection. Toxicology studies with repeat exposures to xenobiotics producing hydrogen peroxide either directly or indirectly generally indicate that the organisms develop resistance to the toxin (adaptation). This adaptation would result from induction of catalase activity in most target organs. The induction of hepatic peroxisomes accompanied by less than compensatory increase in catalase activity is now recognized as suggesting a potential for hepatotoxic and hepatocarcinogenic effects. Although these effects seem to also require mobilization of fatty acids, it is not clear if such mobilization is an absolute requirement. As would be expected, there are great differences among species in catalase activity thus making animal-human extrapolations difficult. Finally, with the exception of premature and neonatal animals, age-related variations in catalase activity do not seem to be large enough to have toxicological relevance. However, in old animals, their apparent inability to replace lost catalase activity after repeated stress may have major significance in explaining observed young-old differences in toxicity resulting from oxidant stress.

Erythrocytes of both G-6-PD deficient humans and Dorset sheep, an animal model with an erythrocyte G-6-PD deficiency, both responded in a dose dependent manner to the oxidant stress of MOHP as measured by decreases in G-6-PD activity, increases in METHB levels and decreases in GSH. However, the human G-6-PD deficient erythrocytes were considerably more sensitive to the formation of METHB than the sheep erythrocytes while the reverse was the case for the GSH parameter. The results suggest a qualitative difference in the response of sheep erythrocytes and human G-6-PD deficient erythrocytes to MOHP that seriously questions the value of the sheep erythrocyte as a quantitatively accurate predictive model.

The U.S. Environmental Protection Agency's (EPA) proposed drinking water standard for radium-226 (226Ra) of 5 pCi/l is evaluated according to its health basis and carcinogenic implications. Proposed health risks of 226Ra in drinking water by other leading theoreticians (Evans, Gofman-Tamplin and Peterson) are also considered in light of the EPA proposal. It is concluded that the EPA proposal to raise the standard for 226Ra in drinking water is not justified on the basis of present knowledge of 226Ra carcinogenic effects.

When exposed to a maximum level of 100 ppm chlorine dioxide in their drinking water, neither A/J or C57L/J mice exhibited any hematologic changes. Chlorite exposure under similar conditions produced increases for red blood cells in osmotic fragility, mean corpuscular volume, and glucose-6-phosphate dehydrogenase activity for both strains. Chlorite exposure of pregnant A/J mice resulted in a significant decrease in the weight of pups at weaning and a lower average birth to weaning growth rate. Mice exposed to as much as 100 ppm sodium chlorite (NaClO2) in their drinking water for up to 120 days failed to demonstrate any histopathological changes in kidney structure.

How the United States and Canada approach the process and implementation of drinking water standards is critically examined. Despite many similarities in their approaches to regulating drinking water contaminants, there are a number of important differences, including approaches to dealing with genotoxic versus presumed epigenetic carcinogens and selection of biostatistical quantitative risk assessment models. Such international comparisons provide a valuable means to discern how others have attempted to solve similar problems and thereby provide an excellent opportunity to test the validity of one's own methodologies.

Since the discovery of superoxide dismutase in 1969, the role of this enzyme in modulating cellular toxicity of superoxide has been well established. Experimentally, cellular damage from compounds or exposures which produce superoxide extracellularly can be prevented or modified by pretreating a cell or organ system with SOD. Likewise, induction of intracellular SOD by exposing the cell system to various types of nonlethal stress will impart resistance or tolerance to further exposures to oxidant and nonoxidant stresses which would normally be toxic. The differences in intracellular SOD activity based on species, age, and organ variability can have a major impact on the interpretation of toxicology data, particularly extrapolation to human toxicology. An awareness of the importance of SOD to the toxicity of xenobiotics which produce superoxide, either directly or indirectly, will enable those conducting toxicology studies to better understand and interpret their results.

A previous study by the current authors demonstrated a statistically significant and clinically important elevation of 3-5 mmHg in mean systolic and diastolic blood pressure in high school sophomores in a community with 108 mg/L of sodium in the water supply when compared to their peers in an appropriately matched community with 8 mg/L of sodium. The current investigation, employing identical techniques but studying third graders in the same two communities, showed similar results. This second look considered dietary intake and urinary excretion of sodium. Since the difference in 24-hour dietary sodium consumption was 300 milligrams between the communities, an intake of one liter of high sodium tap water represented approximately 25 per cent of the difference in total sodium intake between the two communities. These studies suggest that sodium consumption in both drinking water and diet may be contributing to the different blood pressure distributions among the normotensive children in the two communities.

Continuing epidemiologic studies at the University of Massachusetts have examined the hypothesis that elevated levels of sodium (Na) in drinking water contribute to elevations of blood pressure (BP). Comparing tenth graders from a town with 107 mg Na/L in the drinking water to those from a town with 8 mg Na/L, revealed statistically significant and medically important higher BP distributions among the high Na town students relative to their low Na town peers for both systolic and diastolic BP in both boys and girls. The differences were upheld when potentially confounding factors, including dietary Na intake and other water factors occurring differentially in the two water supplies, were controlled in the analysis. A replication study among third graders in the same communities showed similar results. Most recently, an experimental bottled water study assessed the effect on blood pressure of lowering Na concentration in the water of some of the high sodium community fourth graders. For three months trios of children matched by sex, school, and baseline BP each used different water for all cooking and drinking purposes, with BP monitored bi-weekly. Pupils were randomly allocated to the three water conditions: 1) high sodium water bottled from their own community distribution system, 2) low sodium water bottled from the distribution system of the comparison community with sodium added to the level of the high sodium community water and 3) low sodium water bottled from the distribution system of the low sodium community but with no sodium added. Preliminary results indicate the BP levels of the girls on the low sodium water exhibited marked decreases in BP over the test period when compared to the other two groups.

Numerous community drinking water sources have elevated levels of both sodium and lead. Recently reported studies have indicated that elevated levels of sodium in drinking water may be a facter in the development of elevated blood pressure. The question of how elevated levels of lead may affect sodium induced elevated blood pressure is addressed. The hypothesis is developed which states that elevated levels of lead exposure will not interact with sodium to enhance the development of renin angiotensin aldosterone related hypertension but in fact may even diminish the effects of exposure to elevated amounts of sodium on blood pressure through a depression of plasma renin activity.

1. A retrospective epidemiological study was conducted to assess the hypothesis that sex differences exist with respect to selected lead-induced red blood cell parameters. The study utilized data previously collected in the Boston Childhood Lead Poisoning Prevention Program. 2. This study revealed no statistically significant difference between males and females (n = 1548) aged 1-6 years for blood FEP levels when blood lead levels were similar. 3. These findings are in contrast with previously published research with human adults, which has suggested that adult females display significantly greater FEP values at identical blood level values as similarly aged men.

Rats, sheep, and normal humans displayed a comparable sensitivity to copper acetate (3 mM)-induced changes in reduced glutathione (GSH) levels in vitro. However, the human erythrocytes were more sensitive than either animal to methemoglobin (METHB) formation with the rat being least sensitive. Ascorbic acid incubation markedly enhanced the occurrence of copper acetate-induced increases in METHB and decreases in GSH in the sheep and humans. However, ascorbic acid incubation reduced the occurrence of copper acetate-induced increases in METHB, while not effecting changes in GSH in rats.

It is proposed that oral contraceptive (OC) users are at increased risk to experiencing adverse psychological disorders (e.g. irritability, depression) from exposures to elevated levels of carbon disulfide (CS2). This theory is based on studies indicating that both OCs and CS2 induce either a vitamin B6 deficiency and/or enhance its requirement. Since disruptions of B6 metabolism are thought to explain, at least in part, the adverse psychological effects of OCs and CS2, it is speculated that joint exposure to these substances may result in an exaggerated disruption of B6 metabolism with the development of CS2 induced adverse psychological effects occurring at exposure levels below those normally associated with adverse effects.

The problem of organic chemicals in drinking water has been well known since 1974-1975 when the National Organics Reconnaissance Survey (NORS) and the National Organics Monitoring Survey (NOMS) showed that drinking water contaminated by organics could be found throughout the nation. Of special concern are the trihalomethanes (THMs) one of which, chloroform, is a suspected human carcinogen, and has been proven to be carcinogenic in test animals. In addition to chloroform exposure from drinking water, inhalation of chloroform from air while showering may constitute an additional source of exposure. Since the EPA has not included exposure to airborne chloroform in their risk-assessment calculations, the actual cancer risk to the population due to chloroform in drinking water may be significantly higher than the EPA estimated. It is suggested that a major research effort be directed at the determination of airborne chloroform levels in the domestic shower environment. Effort should also be made to determine what variables affect the magnitude of the chloroform levels if present. Once these variables are known it may be possible to educate the public about the potential hazard and ways to eliminate or reduce it.

Individuals with excessive activity of the enzyme ALA-S due to either inherited disorder (i.e. porphyrias) or endogenous (i.e. steroids) or exogenous (e.g. barbituates) chemical agents and who are exposed to elevated levels of lead are predicted to have a significantly enhanced likelihood of experiencing either enhanced or precipitated clinical symptoms (e.g. photosensitivity) associated with elevated levels of porphyrins or their precursors in body tissues. In light of the widespread societal use of ALA-S inducing agents and the ubiquitous nature of lead in the environment, a more precise assessment of the health risks associated with their interaction is warranted.

High school sophomores residing in a community with elevated levels of sodium in the drinking water (107 mg/1) exhibited a marked upward shift in blood pressure distribution patterns for systolic and diastolic blood pressures in both males and females as compared with a similar group in the control community (8 mg/1). The students group from the high sodium community appears to exhibit a blood pressure distribution characteristic of persons several years older.

Fifty-two adult male subjects were randomly assigned to one of three possible treatment groups: supplemental ascorbic acid at one of two levels, 500 mg or 1000 mg, or a placebo. Hair and blood samples were taken before vitamin C or placebo supplementation was started and at monthly intervals thereafter for three months. Samples were analyzed for cadmium, lead, and mercury. Results indicate that vitamin C did not significantly affect levels of these metals in either hair or blood samples.

It has been repeatedly demonstrated that there are considerable interspecies differences with respect to the dermal absorptions of a chemically diverse set of substances, ranging from ionic substances to complex organic molecules, some of which are of great relevance to environmental/occupational health (e.g., the organophosphate insecticides). In general, human skin was found to be much less permeable to the substances evaluated when compared to rabbit and rodent skin; however, the pig and monkey appear to most closely simulate the absorption capabilities of human skin for a variety of substances. Unfortunately, no truly systematic evaluations of numerous classes of compounds have been made via interspecies comparisons. Thus, even though the data derived until now are very consistent, one could argue that strong general conclusions with respect to interspecies differences in dermal absorption cannot yet be made because the substances evaluated thus far may not be sufficiently representative. Clearly, further research along these lines is required.

Continuing epidemiologic studies at the University of Massachusetts have examined the hypothesis that elevated levels of sodium (Na) in drinking water contribute to elevations of blood pressure (BP). Comparing tenth graders from a town with 107 mg Na/L in the drinking water to those from a town with 8 mg Na/L revealed statistically significant and medically important higher BP distributions among the high Na town students relative to their low Na town peers for both systolic and diastolic BP in both boys and girls. The differences were upheld when potentially confounding factors, including dietary Na intake and other water factors occurring differentially in the two water supplies, were controlled in the analysis. A replication study among third graders in the same communities showed similar results.

The effect of age and sex on the elimination of theophylline in New Zealand White rabbits was investigated following exposure to 0.3 ppm of ozone (O3) for 3.75 hr/day over 5 consecutive days. Animals were given air alone 5 to 7 days before and after the 5 days of O3 exposure. The elimination half-life of theophylline was significantly (p = 0.004) prolonged on Days 1 and 5 of O3 exposure in the rabbits greater than 2 years old, with no effect being seen in those 3 to 4 months old. No O3-induced change was seen in the apparent volume of distribution to account for the observed change in theophylline elimination half-life. The female rabbit in particular demonstrated this age-related effect; while in the male, variability prevented the observed difference from reaching significance. The results indicated inhibition of theophylline elimination by O3 in the rabbit depends on age and sex.

Elevated levels of breatheable ozone will reduce the amount of UV radiation in the range of 280-305 nm reaching the surface of earth. This range of UV converts the provitamin 7-dehydrocholesterol to vitamin D, within the human. Since most typical diets contain low levels of vitamin D, the role of UV related vitamin D synthesis in the skin is considered to provide very important contributions to the total vitamin D content of the blood. Thus, elevated levels of ambient ozone should result in a decreased level of vitamin D synthesis which may be expressed as an increase in the incidence of histological osteomalacia and ultimately bone fractures, especially among the elderly.

This paper will provide an introduction to the concept of ecogenetics, including its historical foundations. Specific genetic conditions (more than 30), including those involving RBCs and liver conditions, serum proteins, skin disorders, DNA repair diseases, and others that either theoretically or experimentally have been shown to enhance susceptibility to toxic substances, will be identified and evaluated with respect to their capacity to enhance risk, their frequency in the population, and their ability to be identified in screening tests.

The populations of the developed nations of the world exhibit an increase in blood pressure with age, while in primitive societies blood pressure remains relatively constant throughout adult life. Hypertension may be a complex of diseases all having the same clinical manifestations but not being caused necessarily by the same factors. A possible common denominator in the development of any chronic elevation of blood pressure is the need for the kidney to increase urine volume to promote sodium excretion and, thereby, prevent a chronically expanded extracellular fluid (ECF). Hypertension may be viewed as a maladaptation of the body in its attempt to maintain homeostasis of the ECF. Man evolved under conditions of relative scarcity of salt and even now can maintain normal body function with an intake of less than 2 g/day. The high risk person appears to have a hereditary predisposition to a rise in blood pressure in the presence of a high sodium (NaCl) intake. Actually, the degree of rise in blood pressure may be an interaction between the amount of genetic predisposition and the level of sodium and its relation to potassium intake. Recent work in two Massachusetts communities supports this interpretation and suggests that differences in blood pressure distribution may increase with age between a higher and lower sodium community.

It is proposed that the loss of ability by humans to synthesize ascorbic aicd may have markedly enhanced the survival opportunities of early man living in a malarial infested environment. This hypothesis is based on biomedical evidence which indicates that glucose-6-phosphate dehydrogenase (G-6-PD) deficient individuals display enhanced sensitivity to ascorbic acid induced hemolysis which has been fatal at sufficiently high doses and that the G-6-PD deficient trait has been selected for in malarial environments.