Robert A. Howd

Cancer mortality in a Chinese population exposed to hexavalent chromium in drinking water.

Background: In 1987, investigators in Liaoning Province, China, reported that mortality rates for all cancer, stomach cancer, and lung cancer in 1970–1978 were higher in villages with hexavalent chromium (Cr+6)-contaminated drinking water than in the general population. The investigators reported rates, but did not report statistical measures of association or precision. Methods: Using reports and other communications from investigators at the local Jinzhou Health and Anti-Epidemic Station, we obtained data on Cr+6 contamination of groundwater and cancer mortality in 9 study regions near a ferrochromium factory. We estimated: (1) person-years at risk in the study regions, based on census and population growth rate data, (2) mortality counts, based on estimated person-years at risk and previously reported mortality rates, and (3) rate ratios and 95% confidence intervals. Results: The all-cancer mortality rate in the combined 5 study regions with Cr+6-contaminated water was negligibly elevated in comparison with the rate in the 4 combined study regions without contaminated water (rate ratio = 1.13; 95% confidence interval = 0.86–1.46), but was somewhat more elevated in comparison with the whole province (1.23; 0.97–1.53). Stomach cancer mortality in the regions with contaminated water was more substantially elevated in comparison with the regions without contaminated water (1.82; 1.11–2.91) and the whole province (1.69; 1.12–2.44). Lung cancer mortality was slightly elevated in comparison with the unexposed study regions (1.15; 0.62–2.07), and more strongly elevated in comparison with the whole province (1.78; 1.03–2.87). Mortality from other cancers combined was not elevated in comparison with either the unexposed study regions (0.86; 0.53–1.36) or the whole province (0.92; 0.58–1.38). Conclusions: While these data are limited, they are consistent with increased stomach cancer risk in a population exposed to Cr+6 in drinking water.

Review of the Evidence Regarding the Carcinogenicity of Hexavalent Chromium in Drinking Water

Recent analyses have revealed that 38% of municipal sources of drinking water in California have detectable levels of hexavalent chromium. This observation provided new impetus to characterize the carcinogenic risk associated with oral exposure to hexavalent chromium in drinking water. Notwithstanding the well-characterized increases in cancer associated with inhalation exposure to this chemical, the marked reduction of hexavalent chromium to trivalent chromium in the stomach suggests that exposure to hexavalent chromium in drinking water may not pose a carcinogenic risk. A reevaluation of studies that investigated the toxicokinetics, the genotoxicity, and the mechanism of carcinogenicity of hexavalent chromium, as well as the available human and animal cancer studies, was undertaken to determine if there is evidence that exposure to this chemical in drinking water may pose a carcinogenic risk. Mechanistic studies suggest the potential for a carcinogenic response if hexavalent chromium enters cells. Both toxicokinetic and genotoxicity studies indicate that a portion of an orally administered dose of hexavalent chromium is absorbed and gets into cells of several tissues, causing DNA damage. The only lifetime oral study of hexavalent chromium in animals conducted thus far yielded a statistically significant increase in stomach tumors compared to controls. Also, in a limited-term cancer study, co-exposure to hexavalent chromium in drinking water and ultraviolet light produced skin tumors in mice. The only available cancer study of humans exposed to hexavalent chromium in drinking water revealed a statistically significant increase in stomach tumors. Moreover, a meta-analysis of occupational studies also revealed a statistically significant increase in stomach cancers. The increases in stomach tumors in both human and animal studies, along with the toxicokinetic, genotoxic, and mechanistic data, suggest that oral exposure to this agent appears to pose a carcinogenic risk.

Impact of Smoking and Thiocyanate on Perchlorate and Thyroid Hormone Associations in the 2001–2002 National Health and Nutrition Examination Survey

Background Findings from a recent large study suggest that perchlorate at commonly occurring exposure concentrations may decrease thyroid hormone levels in some women. Decreases in thyroid hormone seen with perchlorate exposure could be even greater in people with concomitant exposure to agents such as thiocyanate that may affect the thyroid by mechanisms similar to those of perchlorate. Objectives and methods We used data from the National Health and Nutrition Examination Survey to assess the impact of smoking and thiocyanate on the relationship between urinary per-chlorate and serum thyroxine (T4) and thyroid-stimulating hormone (TSH). Results In women with urinary iodine levels < 100 μg/L, the association between the logarithm of perchlorate and decreased T4 was greater in smokers [regression coefficient (β) = −1.66, p = 0.0005] than in nonsmokers (β = −0.54, p = 0.04). In subjects with high, medium, and low cotinine levels, these regression coefficients were −1.47 (p = 0.0002), −0.57 (p = 0.03), and −0.16 (p = 0.59). For high, medium, and low thiocyanate tertiles they were −1.67 (p = 0.0009), −0.68 (p = 0.09), and −0.49 (p = 0.11). Clear interactions between perchlorate and smoking were not seen with TSH or with T4 in women with urinary iodine levels ≥ 100 μg/L or in men. Conclusions These results suggest that thiocyanate in tobacco smoke and perchlorate interact in affecting thyroid function, and this effect can take place at commonly occurring perchlorate exposures. Agents other than tobacco smoke might cause similar interactions, and further research on these agents could help identify people who are particularly susceptible to perchlorate.

Community Exposure to a Paraquat Drift

A mixture of paraquat and water was applied, by helicopter, to agricultural fields near a residential community and near an associated commercial complex. Drift from the application passed directly over the community, which resulted in resident complaints to the local county agricultural department. A community survey was undertaken to determine what health consequences, if any, resulted from the drift. A comparison of 2-wk self-reported symptom rates between the exposed community and three historical control communities indicated that 10 symptoms were elevated significantly at p < .05: cough, diarrhea, eye irritation, headache, nausea, rhinitis, throat irritation, trouble breathing, unusual tiredness, and wheezing. An internal comparison, which predicted symptom rates by an index of paraquat exposure (smelling an unusual odor in the prior 2-wk period), indicated fever (relative risk [RR] = 11.97) and nausea (RR = 3.75) to have elevated relative risks. Odor perception also predicted the report of a greater than the average number of symptoms. Based upon these findings, it was concluded that these residents probably did experience an increase in health symptoms from the drift. It is recommended that paraquat not be sprayed near residential communities.

Should Atrazine and Related Chlorotriazines Be Considered Carcinogenic for Human Health Risk Assessment

Chloro-s-triazines have been a mainstay of preemergent pesticides for a number of decades and have generally been regarded as having low human toxicity. Atrazine, the major pesticide in this class, has been extensively studied. In a number of experimental studies, exposure to high doses of atrazine resulted in increased weight loss not attributable to decreased food intake. Chronic studies of atrazine and simazine and their common metabolites show an elevated incidence of mammary tumors only in female Sprague Dawley (SD) rats. On the basis of the clear tumor increase in female SD rats, atrazine was proposed to be classified as a likely human carcinogen by US Environmental Protection Agency (EPA) in 1999. With Fischer rats, all strains of mice, and dogs, there was no evidence of increased incidence of atrazine-associated tumors of any type. Evidence related to the pivotal role of hormonal control of the estrus cycle in SD rats appears to indicate that the mechanism for mammary tumor induction is specific to this strain of rats and thus is not relevant to humans. In humans the menstrual cycle is controlled by estrogen released by the ovary rather than depending on the LH surge, as estrus is in SD rats. However, the relevance of the tumors to humans continues to be debated based on endocrine effects of triazines. No strong evidence exists for atrazine mutagenicity, while there is evidence of clastogenicity at elevated concentrations. Atrazine does not appear to interact strongly with estrogen receptors α or β but may interact with putative estrogen receptor GPR30 (G-protein-coupled receptor). A large number of epidemiologic studies conducted on manufacturing workers, pesticide applicators, and farming families do not indicate that triazines are carcinogenic in these populations. A rat-specific hormonal mechanism for mammary tumors has now been accepted by US EPA, International Agency for Research on Cancer, and the European Union. Chlorotriazines do influence endocrine responses, but their potential impact on humans appears to be primarily on reproduction and development and is not related to carcinogenesis.

Development of a health-protective drinking water level for perchlorate.

We evaluated animal and human toxicity data for perchlorate and identified reduction of thyroidal iodide uptake as the critical end point in the development of a health-protective drinking water level [also known as the public health goal (PHG)] for the chemical. This work was performed under the drinking water program of the Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency. For dose–response characterization, we applied benchmark-dose modeling to human data and determined a point of departure (the 95% lower confidence limit for 5% inhibition of iodide uptake) of 0.0037 mg/kg/day. A PHG of 6 ppb was calculated by using an uncertainty factor of 10, a relative source contribution of 60%, and exposure assumptions specific to pregnant women. The California Department of Health Services will use the PHG, together with other considerations such as economic impact and engineering feasibility, to develop a California maximum contaminant level for perchlorate. We consider the PHG to be adequately protective of sensitive subpopulations, including pregnant women, their fetuses, infants, and people with hypothyroidism.

Irritative and Systemic Symptoms following Exposure to Microban Disinfectant through a School Ventilation System

Microban, a pesticide not registered in California, was sprayed into an operating heating/ventilation/air conditioning (HVAC) unit at an elementary school in San Francisco, California. This incident occurred on Monday, September 28, 1992, while 396 students and 67 staff members were in the school. The Microban formulation used contains ortho-phenylphenol (0.21%), a quaternary ammonium complex (di-isobutylphenoxy-ethoxy-ethyldimethylbenzyl-ammonium chloride, 0.69%), and bromine (0.04%). This study of the health effects of Microban mist exposure on the school staff was conducted as a result of legal and toxicological concerns. California registration for this formulation had been denied because of inadequate data and because there were concerns about inhalation toxicity in test animals. Predicted health effects from short-duration exposure to Microban are primarily skin and mucous membrane irritation. A self-administered health symptom questionnaire that covered the work week following the evacuation was used to determine a pattern of higher symptom risks for those who were at work on Monday and who reported that they felt they were exposed to a chemical. Symptoms, which were generally consistent with exposure to an irritating chemical, were elevated on Monday and Tuesday; the symptoms normalized by the end of the work week. No additional health effects were detected following application of chlorpyrifos to cracks and crevices for ant control 2 d following the Microban incident. Strict supervision and coordination of pesticide use in public schools are recommended to prevent adverse health effects and emotional trauma in students and staff.

Can we protect everybody from drinking water contaminants

Dozens of chemicals, both natural and manmade, are often found in drinking water. Some, such as the natural contaminants uranium and arsenic, are well-known toxicants with a large toxicology database. Other chemicals, such as methyl tertiary-butyl ether (MTBE) from leaking fuel tanks, we learn about as we go along. For still others, such as the alkyl benzenes, there are very little available data, and few prospects of obtaining more. In some cases, chemicals are purposely added to drinking water for beneficial purposes (e.g., chlorine, fluoride, alum), which may cause a countervailing hazard. Removing all potentially toxic chemicals from the water is virtually impossible and is precluded for beneficial uses and for economic reasons. Determination of safe levels of chemicals in drinking water merges the available toxicity data with exposure and human effect assumptions into detailed hazard assessments. This process should incorporate as much conservatism as is needed to allow for uncertainty in the toxicity and exposure estimates. Possible sensitive subpopulations such as unborn children, infants, the elderly, and those with common diseases such as impaired kidney function must also be considered. However, the range of sensitivity and the variability of toxicity and exposure parameters can never be fully documented. In addition, the validity of the low-dose extrapolations, and whether the toxic effect found in animals occurs at all in humans, is never clear. This publication discusses how these competing needs and uncertainties intersect in the development of Public Health Goals for uranium, fluoride, arsenic, perchlorate, and other highly debated chemicals.

Considering changes in exposure and sensitivity in an early life cumulative risk assessment.

A cumulative risk assessment is generally intended to address concurrent exposure by all exposure routes to a group of chemicals that share a common mechanism of toxicity. However, the contribution of different exposure routes will change over time. This is most critical when estimating risks to infants and children because their exposure sources change rapidly during the first few years of life because of dietary and behavioral changes. In addition, there may be changes in sensitivity to toxicants during this time period, associated with various developmental stages. Traditional risk assessments do not address this progression. Examples of how these factors might be incorporated into an early life risk assessment are provided for lead, dioxins and furans, and organophosphate pesticides. The same concepts may apply to other potentially susceptible subpopulations, such as the elderly.

Development of California public health goals (PHGs) for chemicals in drinking water

As part of a program for evaluation of environmental contaminants in drinking water, risk assessments are being conducted to develop Public Health Goals (PHGs) for chemicals in drinking water, based solely on public health considerations. Californias Safe Drinking Water Act of 1996 mandated the development of PHGs for over 80 chemicals by 31 December 1999. The law allowed these levels to be set higher or lower than federal maximum contaminant levels (MCLs), including a level of zero if data are insufficient to determine a specific level. The estimated safe levels and toxicological rationale for the first 26 of these chemicals are described here. The chemicals include alachlor, antimony, benzo[a]pyrene, chlordane, copper, cyanide, dalapon, 1,2‐dichlorobenzene, 1,4‐dichlorobenzene, 2,4‐D, diethylhexylphthalate, dinoseb, endothall, ethylbenzene, fluoride, glyphosate, lead, nitrate, nitrite, oxamyl, pentachlorophenol, picloram, trichlorofluoromethane, trichlorotrifluoroethane, uranium and xylene(s). These risk assessments are to be considered by the State of California in revising and developing state MCLs for chemicals in drinking water (which must not exceed federal MCLs). The estimates are also notable for incorporation or consideration of newer guidelines and principles for risk assessment extrapolations. Copyright