Page 11: Guidelines for Canadian Drinking Water Quality: Guideline Technical Document – Benzene
Part II. Science and Technical Considerations - Continued
Benzene has been classified as a Group 1 carcinogen (carcinogenic to humans) by Health Canada (Environment Canada and Health and Welfare Canada, 1993), the International Agency for Research on Cancer (IARC, 1987), and the U.S. EPA (IRIS, 2003). Although non-cancer effects have been observed in animals exposed to benzene either orally or through inhalation, as well as in humans exposed to benzene occupationally by inhalation, carcinogenicity is considered to be the critical health effect upon which a drinking water guideline should be based. It is important to note that both animals and humans display similar toxic effects following exposure to benzene, regardless of exposure pathway (i.e., via inhalation or ingestion). The most sensitive effects from benzene exposure in both animals and humans are the effects related to the bloodforming organs.
Epidemiological studies were deemed insufficient by Health Canada to serve as the basis for the quantitative estimation of cancer risks from exposure to benzene in the previous drinking water guideline (Health Canada, 1986). The guideline had been developed based on a 2-year cancer study in rats and mice (NTP, 1986), incorporating a surface area correction from rodents to humans and using a robust linear extrapolation model and a standard drinking water consumption rate of 1.5 L/day. Based on this approach, the unit lifetime risk associated with the ingestion of 1 µg benzene/L in drinking water was estimated to range from 6.1 × 10-7 (based on leukaemia and lymphomas in female mice) to 6.7 × 10-6 (based on oral cavity squamous cell carcinomas in male rats).
In 2008, data on the carcinogenic risk to humans following the ingestion of benzene are still not available. The risk to humans can be estimated by extrapolation from human occupational inhalation exposure data. However, because only summary data are available to Health Canada for estimating the unit risk of cancer from benzene exposure, and since animals and humans display similar blood-related effects following benzene exposure, the NTP (1986) study is still deemed to be the best study with which to derive a MAC in drinking water.
Using a linearized multistage model and an allometric scaling factor (to correct for differences in metabolism between animals and humans), the estimated unit lifetime risks associated with ingestion of drinking water containing 1 µg benzene/L are estimated to range from 2.03 × 10-6 to 4.17 × 10-6 (Health Canada, 2005a). The overall unit risk associated with the ingestion of benzene in drinking water is reported as a range, given that lifetime exposure to benzene has been shown to result in more than one cancer end-point in animals. The above unit risk range has malignant lymphoma in female mice (2.03 ×10-6 ) as its lower bound (least sensitive) and bone marrow haematopoietic hyperplasia (4.17 × 10-6) in male mice as its upper bound (most sensitive). These unit risks assume 3.5 L-eq/day as the human drinking water consumption rate in order to account for additional uptake of benzene through dermal and inhalation exposure, estimated using Krishnan (2004).
Since the 1986 guideline, evidence for benzene's leukaemogenic potential in humans has been reported by many authors for workers occupationally exposed to benzene by inhalation. The Ohio Pliofilm cohort (Rinsky et al., 1981, 1987; Crump and Allen, 1984; Paustenbach et al., 1993; Paxton et al., 1994) and Chinese worker cohort studies (Yin et al., 1987, 1994, 1996; Dosemeci et al., 1994, 1996) have emerged as good studies for assessing the carcinogenic potential of benzene in humans following inhalation exposure in the workplace. In developing its public health goal for benzene in drinking water, the California Environmental Protection Agency (CalEPA) reanalysed the Ohio Pliofilm and Chinese worker cohort data (OEHHA, 2001). For the Pliofilm cohort, original data were obtained, allowing for a thorough sensitivity analysis of several outstanding issues identified in the literature, including choice of exposure matrix, start date for determining person-years at risk, worker subset, choice of model, and choice of background incidence rates for calculating lifetime risks. CalEPA was unable to obtain a full set of data for the Chinese worker cohort. As a result, grouped summary data published by the original study author (Hayes et al., 1997) were used, which did not allow for a complete analysis.
In a detailed assessment of the CalEPA analysis, Health Canada agreed with its balanced approach and thorough consideration of the outstanding issues identified above. With only summary data available to Health Canada for reassessment of the two cohort studies, no new follow-up data since the CalEPA assessment, and thorough analysis of these two cohorts by many other international authors, it was concluded that another new analysis using virtually the same approach would be redundant. The only change necessary to the CalEPA analysis would be to use Canadian standard death rates to calculate the lifetime risk of cancer instead of using U.S. or Californian death rates. Given the expected similarity of Canadian leukaemia death or incidence rates and those in the United States and California, this change would have a minimal impact on the lifetime risk estimates (Health Canada, 2005b).
In using CalEPA's estimated unit risks of leukaemia for ingestion of benzene, which were extrapolated from the Pliofilm and Chinese cohort inhalation data, Health Canada estimated the lifetime risks associated with ingestion of 1 µg/L of benzene in drinking water as 4.8 × 10-6 (95% CI) from the Pliofilm cohort and 6.3 × 10-6 (95% CI) from the Chinese worker cohort. Once again, these estimated lifetime risks fall within the range considered to be
"essentially negligible" and are comparable to the unit lifetime risks estimated from the animal data. These unit lifetime risks assume 3.5 L-eq/day as the human drinking water consumption rate (in order to account for inhalation and dermal exposure). Inhalation unit risks were converted to unit risks for ingestion using a standard body weight of 70 kg, a breathing rate of 20 m3/day, an inhalation absorption rate of 50%, and a conversion factor of 1 ppm = 3190 µg/m3 of air (OEHHA, 2001).
In humans, the haematopoietic cancer induced by benzene exposure is predominantly acute non-lymphocytic leukaemia; in rodents, lymphocytic leukaemia has been reported in mice (Snyder et al., 1980; NTP, 1986; Cronkite et al., 1989). The difference in induction of haematopoietic cancers in mice and humans is not yet clear; however, it may be due to differences in haematopoiesis between the two species. In mice, lymphocytes make up a larger portion of the nucleated cells in the bone marrow compared with humans (Parmley, 1988); therefore, lymphocytic leukaemia in mice could simply be the result of lymphocytes representing a larger target cell population for benzene metabolites in the bone marrow. Further research into the mechanism of lymphoma and leukaemia development in animals and humans following exposure to benzene is needed.
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