Incorporating biologically based models into assessments of risk from chemical contaminants.

The general approach to assessment of risk from chemical contaminants in drinking water involves three steps: hazard identification, exposure assessment, and dose-response assessment. Traditionally, the risks to humans associated with different levels of a chemical have been derived from the toxic responses observed in animals. It is becoming increasingly clear, however, that further information is needed if risks to humans are to be assessed accurately. Biologically based models help clarify the dose-response relationship and reduce uncertainty.

Drinking water health advisory program.

The US Environmental Protection Agency prepares Health Advisories (HA) for drinking water contaminants. The HA provide technical guidance to public health officials or other interested groups on many aspects concerning drinking water contamination. The HA contain information on the chemistry, health effects, analytical methods and treatment technologies for specific contaminants. In addition, the HA include a risk assessment section which provides concentrations of the contaminant in drinking water that are not anticipated to cause adverse, noncancer health effects for 1 or 10 days or for longer exposures. Because the HA include risk assessments for less than lifetime exposures, they are useful when accidental spills occur or when regulatory limits are temporarily exceeded. The guidance documents are updated when new information becomes available that would change the previous conclusions.

Non-carcinogenic effects of inorganic arsenic.

This review will focus primarily on ohe effects of the inorganic arsenicals (arsenate and arsenite forms) that are present in drinking water. They are acutely toxic to both humans and animals, an effect that may be related to their bioavailibility. In humans, arsenicals have been reported to cause dermatitis and mucous membrane irritation upon exposure. They have also been reported to cause skin lesions and peripheral neurotoxicity in smelter workers and in patients treated with Fowler's Solution. When humans are exposed to arsenic in drinking water, effects such as hyperkeratosis, electromyographic abnormalities and vascular effects have been reported. In experimental animals, arsenic has been demonstrated to affect the liver and kidneys. In mice, arsenic has also been reported to decrease the animal's resistance to certain viral infections. The arsenite (+3) and arsenate (+5) forms have different modes of action. Arsenite binds to sulphhydryl groups and has been reported to inhibit over 100 different enzymes, while the arsenate can substitute for phosphate in various high energy intermediates, resulting in arsenolysis. In addition, when arsenate is reduced to arsenite in the body, it can also cause toxicity as that species.

Assessing the health risks of aluminum.

Aluminum is a ubiquitous substance with over 4,000 uses. Aluminum, as aluminum sulfate, is commonly used in the United States as a coagulant in the treatment of drinking water. For many years aluminum was not considered to be toxic to humans. However, reports associating aluminum with several skeletal and neurological disorders in humans suggest that exposure to aluminum may pose a health hazard. In 1983 the US Environmental Protection Agency (EPA) announced plans to regulate a number of substances, including aluminum, in drinking water. Aluminum was considered because of its occurrence and apparent toxicity. Upon further evaluation of the health effects data the EPA proposed not to regulate aluminum as a result of the uncertainty of the toxicity of ingested aluminum. Putative causal associations between aluminum exposure and neurological disorders such as Alzheimer's disease have yet to be substantiated. Although several issues regarding the toxicity of ingested aluminum are unresolved, aluminum has been specified in the 1986 Amendments to the Safe Drinking Water Act, as one of 83 substances in drinking water to be regulated by 1989. Additional data are needed before the potential risk of aluminum can be assessed; therefore the EPA has deferred possible regulation until 1991.

Problems in assessing the risks of mixtures of contaminants in drinking water.

In conducting risk assessments on drinking water contaminants, the U.S. Environmental Protection Agency (EPA) attempts to evaluate all available toxicity data to develop Health Advisory (HA) and Maximum Contaminant Level Goal (MCLG) values. The EPA often has grappled with the issues surrounding the toxicity of chemical mixtures, including radioactive contaminants, nitrate/nitrite, and trihalomethanes (THMs). In evaluating the toxicity of chemical mixtures, the EPA's immediate concern is whether the individual HA values and MCLGs are protecting public health when multiple contaminants are present in drinking water. Potential toxic interactions between drinking water contaminants are difficult to predict because experimental studies are generally performed only at high doses relative to environmental levels. Although the contamination of drinking water involves mixtures of contaminants, drinking water regulations are generally based on an assessment of the risks of individual contaminants. This paper discusses three issues of major concern to the EPA: the synergistic effects of solvent mixtures, vehicle effects in laboratory studies, and setting standards for essential trace nutrients where the absorption and/or toxicity are affected by an individual's nutritional status or other dietary components.

Summation from a regulatory perspective.

There is an urgent need to discuss the Office of Drinking Water's standard-setting or rulemaking process since most of the researchers whose papers are presented here directly or indirectly play a crucial role in this complex undertaking. Therefore, this paper will address the research data required to support policymaking and regulatory decisions pertaining to health effects of disinfectants and disinfection by-products.

Etiological role of cadmium in hypertension in an animal model.

Dahl hypertension-resistant (R) and hypertension-sensitive (S) lines of rats were used to determine whether cadmium plays an etiological role in hypertension. In Study I, weanling (3-week-old) R and S rats of both sexes were given a low-salt (0.4% NaCl) diet and were divided into two groups. Rats in the cadmium group were injected with cadmium (2 mg/kg body weight, ip), whereas the controls received identical volumes of saline. Three weeks after the first injection, no elevations of systolic blood pressure were detected. A second dose of cadmium (1 mg/kg) produced hypertension in S females but not in S males or in R rats of either sex. Also, female S cadmium rats manifested significant (p less than 0.01) mild to moderate renal vascular changes. The concentrations of cadmium in hepatic and renal tissues of S cadmium rats were significantly higher (p less than 0.001) than in R rats. In Study II, weanling (3-week-old) female S rats on a high-salt (4% NaCl) diet were given cadmium (2 mg/kg body weight, ip) at week 3 followed by second and third injections of cadmium (1 mg/kg) at weeks 6 and 23. S controls received the same volumes of saline. Cadmium enhanced the rate and the degree of salt-induced hypertension development. Pathological lesions of periarteritis nodosa in the mesenteric arteries and renal vascular lesions occurred to the same extent in the cadmium and control groups. These data indicate that differences in genetic background influence the development of cadmium-induced hypertension in weanling rats, and that cadmium exacerbates the severity of salt-induced hypertension.

Effects of cadmium ingestion in rats with opposite genetic predisposition to hypertension.

This study was undertaken to explore the effects of chronic low-level cadmium ingestion in Dahl hypertension-resistant (R) and hypertension-sensitive (S) lines of rats. Groups of weanling female R and S rats were given 0 or 1 mg cadmium/1. in drinking water and fed either a low salt (0.4% NaCl) or a high salt (4% NaCl) diet for 28 weeks. Cadmium produced hypertension associated with gross cardiac hypertrophy and mild to moderate renal vascular changes in S, but not in R, rats on a low salt diet. Cadmium enhanced the rate and degree of development of salt-induced hypertension without exacerbating the hypercholesterolemia or renal vascular lesions normally observed in S rats on a high salt diet. Cadmium lowered circulating cholesterol levels in both lines on a low salt diet. Cadmium had no influence on growth, blood urea nitrogen concentration, plasma renin activity, tumor formation, or survivorship in R and S rats on either salt diet. This study indicates that the genetic composition is a critical determinant of the adverse effects of chronic low-level cadmium ingestion in rats. In addition to the experimental implications, these findings may have relevance to the problem of human "essential" hypertension.

Genetic influence on cadmium-induced hypertension.

Dahl hypertension-resistant (R) and hypertension-sensitive (S) rats were used to determine whether cadmium-induced hypertension is dependent on genetic predisposition. In experiment I, 16 wk-old R and S rats of both sexes were injected with two doses of cadmium (1 and 2 mg/kg body wt, ip), whereas the controls received the same volumes of saline. Hypertension and renal vascular changes were observed in cadmium-injected S rats but not in R rats. The S females appeared more sensitive than S males to the hypertensinogenic effect of cadmium. In experiment II, groups of weanling female R and S rats were given 0, 1, 2.5, 5, or 10 mg cadmium/liter drinking water and fed either a low-salt (0.4% NaCl) or a high-salt (4% NaCl) diet for 28 wk. Cadmium produced cardiac hypertrophy (1 mg cadmium/liter) and hypertension associated with renal vascular changes (1--5 mg cadmium/ liter), and it enhanced proteinuria (1-10 mg cadmium/liter) in S rats on a low-salt diet. Also, the development of salt-induced hypertension was accelerated in cadmium-fed (1 and 2.5 mg/liter) S rats. These adverse effects of cadmium were not detected in R rats on either salt diet. In experiments I and II, cadmium concentrations in the kidneys and liver of S rats were higher (P less than 0.001) than in those of R rats. These data indicate that genetic differences influence the pathogenesis of cadmium-induced hypertension.

Influence of thiazide on salt hypertension.

This study was undertaken to evaluate the effect of chronic diuretic therapy with chlorothiazide on the course of salt hypertension in hypertension-resistant (R) and hypertension-sensitive (S) strains of rats. Investigation of the effects of chlorothiazide on blood pressure, 24-hour urinary 24Na and aldosterone excretion, and plasma renin activity (PRA) produced the following observations: (1) Chlorothiazide failed to prevent the development of salt hypertension in S rats. (2) After 12 weeks, S rats on high salt puls chlorothiazide exhibited a rapid fall in blood pressure to levels indistinguishable from those of S rats on low salt. (3) Chlorothiazide significantly increased urinary 24Na excretion only in S rats on high salt (P less than 0.01). (4) Chlorothiazide significantly increased PRA and urinary aldosterone excretion in both strains on low or high salt diets (P less than 0.001). (5) Morbidity and mortality of salt hypertension were alleviated by chlorothiazide treatment. The unique aspect of this study is the finding that chlorothiazide did not abolish the hypertensiogenic action of salt in S rats.

Role of the gonads in hypertension-prone rats.

In a genetically hypertension-prone (S) strain of rats it was observed previously that males generally developed hypertension more rapidly on a high salt diet than did females although final pressure ultimately were similar in both sexes. A genetic study had shown that there was no sex-linkage involved in setting blood pressure levels, so it was thought that the gonads might be involved. In the present work, castration of males had no effect on blood pressure but in the females it caused a rise in pressure that could not be distinguished from that in males, both on a high and low salt diet. Castration resulted in greater growth in females than in controls, whereas it had the opposite effect in males. It was speculated that these changes were due to influences on pituitary growth hormone with castration increasing the net output of growth hormone (or enhancing receptor sensitivity to it) in the female and the opposite in the male. From the work of others, there are some data compatible with such an interpretation. Experimentally, growth hormone will induce hypertension in rats. Therefore, it is conceivable that growth hormone is involved in the increment in hypertension observed in these castrate females. Because the effect on blood pressure was observed in castrate females on both high and low NaCl diets, it was considered unlikely that the blood pressure effect was simply due to increased NaCl intake in the food associated with greater growth. It was suggested that this rise in blood pressure with cessation of ovarian function might bear on the unsettled question of "menopausal" hypertension in women: in the genetically susceptible individual an increase in growth hormone associated with declining ovarian funtion in the menopause could provide the stimulus for the appearance of hypertension some years earlier than would otherwise have been the case.