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1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver, and kidney damage at sufficiently high exposure levels. Two physiologically based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed: partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassay conditions. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.

A population-linked database was used to assess exposure to the herbicides atrazine and simazine in drinking water provided by community water systems (CWS) in 21 major use states. Herbicide concentration and population data from 1993 through 1995 were paired for each CWS and aggregated for all CWS to construct state and multi-state exposure profiles. The assessed populations were 110 million for atrazine and 107 million for simazine. The majority of the CWS population had no detectable exposure to atrazine and simazine. All simazine and 99.9% of atrazine populations had exposure below their respective drinking water MCLs. Thirteen of 13,688 CWS had atrazine multi-year mean concentrations above the MCL ranging from 3.06 to 6.19 ppb. Exposures to atrazine and simazine both corresponded to a margin of safety of at least 10,000 for 94% and 96% of the assessed population. Ciba Crop Protection (Ciba) is continuing this monitoring program at least through 1997 to provide a 5-year database, and will update this assessment with 1996 and 1997 data.Atrazine (2-chloro-4-ethylamino-6-isopropyl-amino-s-triazine) and simazine (2-chloro-4,6,bis(ethylamino)-5-triazine) are triazine herbicides (1). Both exhibit herbicidal activity on certain annual broadleaf and grass weeds through inhibition of photosynthesis. In the United States, annual atrazine use is the greatest on corn (83%) followed by sorghum (11%) and sugarcane (4%). Atrazine and simazine annual use in the 21 major use states (Figure 1) account for 92% and 91% of the U.S. use, respectively (2). Simazine is used less extensively than atrazine on corn. 252

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