Dose-response relationships drinking water

Increased mortality was observed in a 2-year feeding study in rats (Azar et al. 1973). However, the increased mortality did not occur in a dose-related manner. The apparent lack of a dose-response relationship in either sex precludes meaningful conclusions regarding effect levels for mortality in this study. Increased mortality was reported in mice exposed to 0.5% lead acetate in the drinking water in a 3-generation study (Rasile et al. 1995). This level of lead in the water provided approximately 605 mg lead/kg/day. 

Yoshida, T., Yamauchi, H., and Sun, G.F., Chronic health effects in people exposed to arsenic via the drinking water Dose-response relationships in review, Toxicol. Appl. Pharmacol., 198, 243, 2004. 

The carcinogenicity of orally administered phenol was examined in rats and mice in a study reported by the National Cancer Institute (NCI 1980). Rats and mice received 0, 2,500, or 5,000 ppm in drinking water for 103 weeks. Calculated intakes for rats were 322 and 645 mg/kg/day for males and 360 and 721 mg/kg/day for females. Calculated intakes for mice were 590 and 1,180 mg/kg/day for males and 602 and 1,204 mg/kg/day for females. Statistically significant increased incidences of pheochromocytomas of the adrenal gland and leukemia or lymphomas were observed in male rats exposed to 322 mg/kg/day (2,500 ppm), but not in male rats exposed to 645 mg/kg/day (5,000 ppm). No significant effects were seen in female rats or mice of either sex exposed to either exposure level. Since cancer occurred only in males of one of the two species tested and a positive dose-response relationship could not be established, these results are inconclusive regarding the carcinogenic potential of orally administered phenol. 

No information is available on the effects of intermediate-duration oral exposure in humans, but two animal studies (Boorman et al. 1986 Danse et al. 1984) provide sufficient data to identify the main target tissue (the stomach epithelium) and to define the dose-response relationship for this effect. These studies are suitable for derivation of an intermediate oral MRL, but further studies would still be helpful to search more specifically for possible subclinical neurological effects. This is important since neurological effects appear to be the most sensitive effect by the inhalation route, and people may be exposed to low levels of bromomethane in drinking water drawn from contaminated groundwater sources. No information is available on intermediate- duration dermal exposure to bromomethane. However, humans are not likely to experience significant dermal exposures to bromomethane near waste sites, so research in this area does not appear to be essential. 

Further data on the effects of chronic inhalation exposure to 1,4-dichlorobenzene would be useful, especially because chronic exposures to 1,4-dichlorobenzene in the air, in the home, and the workplace are the main sources of human exposure to this chemical. Any further testing of the effects of chronic exposure to 1,4-dichlorobenzene via the oral route should probably be done at lower levels of 1,4-dichlorobenzene than those that have already been used in the NTP (1987) bioassay, and should focus on dose-response relationships involving the hepatic, renal, hematopoietic, central nervous system, and metabolic pathways. Data on the effects of chronic dermal exposure to 1,4-dichlorobenzene may be useful if dermal absorption and systemic distribution of 1,4-dichlorobenzene can be demonstrated from toxicokinetic studies, since chronic dermal exposure to 1,4-dichlorobenzene occurs as a result of bathing and showering in drinking water that contains low levels of this chemical in many U.S. communities. 

Atherosclerosis is a pathogenic response of the intima of the arterial vessel walls to noxious stimuli. It is characterized by lipids depositing in the vessel walls, which leads to wall narrowing. This can progress to IHD. Exposure to arsenic in drinking water is associated with an increased prevalence of carotid atherosclerosis in a dose-response relationship. In a cross-sectional study, Wang et al. (2002) assessed... 

In an ecological study of a population in southwest Taiwan, Wu et al. (1989) reported a significant dose-response relationship in age-adjusted mortality from bladder cancer. In males, the mortality rates (per 100,000) were 23, 61, and 93 and for females the rates were 26, 57, and 111 for mean arsenic levels of <0.3, 0.3-0.59, and 0.6 mgL-1 in drinking water. 

The evidence for the carcinogenicity of formaldehyde in rats exposed to formaldehyde-containing drinking water is not strong due to inconsistency of findings across studies and inconsistent evidence of a dose-response relationship for either leukemia or gastrointestinal tumors in the Soffritti et al. (1989) study. 

Adult mice Dosing Pb in drinking water, 200 or 500 ppm for 14 or 30 days Dose—response relationship P5N versus PbB in erythrocytes and bone marrow Inhibition of P5N activity significantly increased 25% in marrow cells, 45% in erythrocytes Tomokuni et al. (1989)... 

Adult male wild-type or metallothionein-l/ll knockout mice Pb acetate in drinking water 0, 1,000, 2,000, 4,000 ppm started at 8 weeks, dosed for 112 weeks Wild-type mice showed a dose—response relationship in renal proliferative lesions and tumors Waalkes et al. (2004)... 

Dose—Response Relationships in Humans for Drinking Water Pb Relevant to Regulation... 

Yoshida, Takahiko, Hiroshi Yamauchi, and Gui Fan Sun. 2004. Chronic Health Effects in People Exposed to Arsenic Via the Drinking Water Dose-Response Relationships in Review. Toxicology and Applied Pharmacology 198 243-252. 

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