2002 SOT Meeting held March 18-21, 2002 in Nashville, TN

NOAEL/LOAEL and Benchmark Dose Approaches to Setting Acceptable Human Exposure Levels to 1,2-Dichloroethane (Ethylene Dichloride)

Abstract
Chemical risk assessment approaches other than the most common NOAEL/LOAEL approach are being considered by the EPA. The benchmark dose (BMD) approach has a number of advantages to the traditional NOAEL/LOAEL approach, including not being limited to the experimental doses, and responding to sample size and the associated uncertainty. Because EPA's IRIS database contains no reference dose for chronic oral exposure (RfD) for 1,2-dichloroethane, multiple approaches were compared for derivation of a provisional toxicity value. The majority of 1,2-dichloroethane released into the environment enters the atmosphere from its production and use as a chemical intermediate, solvent, and use as a lead scavenger in gasoline. Major human exposure is from urban air, drinking water from contaminated aquifers and occupational atmospheres. Animal studies point to the kidney and liver as target organs for 1,2-dichloroethane toxicity, consistent with reported injury to these organs in humans following accidental acute ingestion. The principal study selected as the basis for RfD derivation was conducted in rats and used five concentrations in drinking water, ranging from 500-8000 ppm, and a vehicle control. The lowest exposure level was considered a minimal LOAEL for increased kidney weight. Because the principal study examined a sufficient number of exposure levels, an RfD was also calculated using a BMD approach. RfD comparisons were based on several endpoints including increased kidney and liver weights, renal and liver histopathology, and altered enzyme activities.

Abstract
A review of the available carcinogenicity data for BBP (CASRN 85-68-7) identified the chemical as a candidate for analysis of carcinogenic risk by both the traditional linear method as well as the proposed nonlinear (margin of exposure) method. Currently, BBP is classified as Group C (Possible Human Carcinogen) based on no human data and limited animal data. The basis for this classification is a 1982 NTP study wherein a statistically significant increase in mononuclear cell leukemia was reported in female rats following two years of exposure to 12,000 ppm of BBP in the feed. A quantitative estimate of carcinogenic risk from oral exposure is not currently included on IRIS due to the qualitative weakness of the response, including similar pathologies in the control and treated groups and lack of reduction in time to first tumor. More recently, NTP conducted additional long-term feeding studies with BBP in F344 rats. The results of these studies provided some evidence of an increase in the incidence of pancreatic cancer in male F344 rats, though a significant increase was only seen at the highest exposure level (12,000 ppm). Concurrent with these neoplastic lesions, the study reported a dose-dependent increase in preneoplastic lesions (acinar hyperplasia) in the pancreas. The mode(s) of action of BBP-induced carcinogenesis are not clear. There is limited evidence supporting both genotoxic and non-genotoxic mechanisms. The majority of data from genotoxicity testing have indicated that BBP is not strongly genotoxic. Moreover, BBP, like other phthalate diesters, induces peroxisome proliferation, which is the putative mechanism of action for the observed changes in the pancreas. A comparison of the results using the default linear approach and a nonlinear (margin of exposure) approach provides insight into the effect of linearity assumptions in deriving of quantitative estimates of oral carcinogenic risk for BBP.

Abstract
A review of the available carcinogenicity data for p-chloroaniline identified the chemical as a candidate for analysis of carcinogenic risk by both the traditional linear method as well as the proposed nonlinear (margin of exposure) method. Although no human carcinogenicity data are available, published chronic oral studies in rats and mice provide evidence of multi-organ carcinogenicity. The cancer risk assessment for p-chloroaniline is complicated by species differences in target organ susceptibility and uncertainty as to which of the compound's possible carcinogenic mechanisms is most relevant to humans. There is evidence for genotoxic and non-genotoxic modes of action, both of which apparently require bioactivation of p-chloroaniline. The primary tumor types observed in the oral studies are rare splenic tumors (fibrosarcoma, osteosarcoma, or hemangiosarcoma) and adrenal medullary pheochromocytomas in male rats, and hepatocellular carcinomas in male mice. Data on tissue-specific distributions of reductase activities, which protect against the reactive intermediates of p-chloroaniline, suggest that the mouse hepatocellular tumors may not be relevant to humans. However, either of the rat tumors could be relevant to humans: the adrenal tumors induced by a genotoxic mechanism, and the splenic tumors induced by a non-genotoxic mechanism secondary to erythrocyte toxicity. Dose-response modeling of the incidence data for rat tumors was performed using both linear and non-linear methods. In deriving oral slope factors based on rat adrenal and splenic tumors, the default approach assuming linearity was compared with the margin of exposure approach, which assumes nonlinearity. The margin of exposure approach for splenic sarcomas was based on the assumption that an oral dose of p-chloroaniline that was protective for splenic fibrosis (a non-neoplastic lesion) would also be protective for carcinogenicity in the spleen.

Abstract
U.S. EPA is currently re-evaluating the RfD for zinc. Derivation of an RfD for zinc requires balancing its essentialty functions with its potential adverse effects. Essential trace elements, such as zinc, pose an additional problem of nutrient-nutrient interactions. The excessive intake of one nutrient may interfere with the toxicokinetic properties of another nutrient. Increased zinc intake has been associated with a number of adverse health effects in humans, including decreased erythrocyte Cu-Zn superoxide dismutase (ESOD) activity, hematological effects, decreases in HDL-cholesterol levels, and gastrointestinal effects. Human studies provide evidence that excessive zinc intake may primarily induce copper deficiency. Excessive dietary zinc results in the induction of intestinal metallothionein synthesis. Since metallothionein has a greater binding capacity for copper than for zinc, copper absorbed into the intestinal mucosal cells is sequestered by metallothionein and does not enter the body. Copper deficiency is the primary mechanism for a number of the effects associated with excessive zinc intake, including decreases in HDL-cholesterol levels and ESOD activity. The endpoints associated with copper deficiency appear to be the most sensitive targets of toxicity (occur at doses of Zn as low as 300 ppm). There are limited data to suggest that high zinc intake can decrease iron absorption leading to symptoms of iron deficiency. In deriving an RfD for zinc, these interactions, as well as others, must be considered to determine a level of zinc (4-40 mg/day) that would not result in a disturbance in the balance of other nutrients. (This abstract does not necessarily reflect U.S. EPA policy).

Abstract
Toluene is widely used in industry as a solvent, gasoline additive, and in polymer production. The present EPA assessments for toluene on IRIS were verified between 1987 and 1990. Since the verification dates, a number of new studies have been published, warranting a reconsideration of the data for toluene. The existing IRIS RfD is based on hepatic effects in rats exposed by gavage. New oral studies not described on IRIS examined hepatic, immunological, and neurological endpoints, and raise the issue of whether or not to change the critical effect for RfD derivation from hepatic effects to one based on immunological or neurological endpoints. The existing RfC is based on a LOAEL for neurobehavioral effects in a study of toluene-exposed electronics workers, but a number of new studies examining neurologic effects in occupationally-exposed humans have been published, including two identifying NOAELs. The new studies support neurological effects as the critical effect for RfC derivation and add more information about exposure-response relationships. Several methods of analysis, including NOAEL/LOAEL and benchmark dose analyses, are under consideration with regard to the derivation of a new RfC. New data are also available examining the potential carcinogenic effects of toluene. While a single oral study in rats has suggested carcinogenic effects of toluene, limited reporting of the study results confounds interpretation. Adequate inhalation bioassays in rats and mice have not demonstrated a carcinogenic effect of toluene, and the vast majority of genotoxicity evaluations of toluene have been negative. (This document does not necessarily reflect EPA policy.)

Abstract
Tributyl phosphate (TBP) is a non-flammable, non-explosive liquid that is used as a solvent or an anti-foaming agent. Dietary exposure to tributyl phosphate at high doses produces a reversible hyperplasia of the urinary bladder epithelium which is not due to the presence of crystalluria, urinary precipitates or calculi, but may possibly be attributed to the presence of a toxic metabolite(s), tertiary butyl alcohol and or dibutyl hydrogen phosphate. A 2-year study of rats and mice identified both a NOAEL and LOAEL for bladder hyperplasia in rats, and was selected as the key study for the derivation of the provisional RfD. Mice did not show significant dose-response in any of the target organs examined in this 2-year chronic study. The 2-year rat study reported a significant increase of urinary bladder papillomas and carcinomas in males and urinary bladder papillomas in females, but only in animals exposed to the highest level of TBP in their diet. There is no clear evidence for the mode(s) of action for tributyl phosphate-induced urinary bladder tumors in rats. The vast majority of in vitro and in vivo tests indicate that tributyl phosphate is negative for genotoxicity. The apparent lack of genotoxic effects, coupled with low-dose hyperplasia and high-dose tumor formation, is suggestive of a non-genotoxic mechanism of carcinogenesis. Therefore, several different approaches were used when calculating a quantitative estimate of carcinogenic risk. Provisional oral slope factors were derived using both a linearized multistage model and a margin of exposure analysis, and the results produced by the different methods were compared. (This abstract does not necessarily reflect EPA policy).

Abstract
The brominated trihalomethanes (BTHMs) bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform are by-products of drinking water chlorination. Information on the hazard, dose-response, and risk characterization of these chemicals is being updated. Oral Reference Doses (RfDs) for BDCM, DBCM, and bromoform have previously been derived using the conventional NOAEL/LOAEL approach and are reported in the Integrated Risk Information System (IRIS). The RfDs obtained were 0.02 mg/kg-day for BDCM, based on lesions in the liver, kidney, and thyroid of exposed mice; 0.02 mg/kg-day for DBCM, based on absence of lesions in exposed rats; and 0.02 mg/kg-day for bromoform, based on absence of effects in exposed rats. For the updating process, new health effects data published between 1993 and July, 2001 were identified and evaluated. Toxicological endpoints from new and existing studies were reviewed for suitability for benchmark dose modeling. Benchmark doses (BMDs) for selected endpoints were obtained using the Benchmark Dose Modeling Software (Version 1.2) developed by the U.S. EPA National Center for Environmental Assessment. BMDL₁₀ values (the 95% lower confidence limit on the BMD) were used to calculate a new RfD for each BTHM. The uncertainty factors used in derivation of the RfD values were also re-evaluated in consideration of new studies added to the databases for individual BTHMs. Using this approach, the resulting RfD values are 0.003 mg/kg-day for BDCM, based on fatty degeneration in the liver of rats; 0.02 mg/kg-day for DBCM, based on fatty changes in the liver of rats; and 0.009 for bromoform, based on hepatocellular vacuolization in the liver of rats. (This work was conducted under contract to EPA, but the opinions expressed in this abstract are those of the authors and do not necessarily represent EPA policy.)

Abstract
Previous evaluations of the experimental toxicity data for ethylene dibromide (EDBr) have concluded that limitations of the available studies precluded the derivation of oral toxicity values. Therefore, the the U.S. EPA has no oral RfD on IRIS and ATSDR has not developed an MRL for EDBr. Upon critical re-examination of the data, however, with consideration of the strengths and limitations of the existing studies, as well as a proposed mechanism of action for the testicular effects of EDBr, a provisional oral RfD for EDBr of 9x10^-3 mg/kg-day is presented here. A lifetime carcinogenicity study in rats and mice was performed by the NCI, but was terminated prematurely because the MTD was apparently being exceeded. Even with early termination, dose-related increases in testicular atrophy were noted histologically, as well as increased incidence of tumors of the tunica vaginalis (the serous covering of the testes). Several studies in bulls exposed orally to low doses of EDBr also showed testicular atrophy, which was reversible upon cessation of exposure. Rodent studies of 90 days and 17 months have also examined the oral toxicity of EDBr. The provisional RfD is based on testicular atrophy in rats observed in the NCI study rather than on the effects observed in bulls at lower doses. The rationale for the choice of critical study includes an allometric argument as well as a mechanistic one.