Development of an inhalation unit risk factor for isoprene.

A unit risk factor (URF) was developed for isoprene based on evaluation of three animal studies with adequate data to perform dose-response modeling (NTP, 1994, 1999; Placke et al., 1996). Ultimately, the URF of 6.2E-08 per ppb (2.2E-08 per µg/m(3)) was based on the 95% lower confidence limit on the effective concentration corresponding to 10% extra risk for liver carcinoma in male B6C3F1 mice after incorporating appropriate adjustment factors for species differences in target tissue metabolite concentrations and inhalation dosimetry. The corresponding lifetime air concentration at the 1 in 100,000 no significant excess risk level is 160 ppb (450 µg/m(3)). This concentration is almost 4400 times lower than the lowest exposure level associated with statistically increased liver carcinoma in B6C3F1 mice in the key study (700 ppm in Placke et al., 1996) and is above typical isoprene breath concentrations reported in the scientific literature. Continuous lifetime environmental exposure to the 1 in 100,000 excess risk level of 160 ppb would be expected to raise the human blood isoprene area under the curve (AUC) less than one-third of the standard deviation of the endogenous mean blood AUC. The mean for ambient air monitoring sites in Texas (2005-2014) is approximately 0.13 ppb.

Development of an inhalation unit risk factor for hexavalent chromium.

A unit risk factor (URF) was developed for hexavalent chromium (CrVI). The URF is based on excess lung cancer mortality in two key epidemiological studies of chromate production workers. The Crump et al. (2003) study concerns the Painesville, OH worker cohort, while Gibb et al. (2000) regards the Baltimore, MD cohort. A supporting assessment was also performed for a cohort from four low-dose chromate plants (Leverkusen and Uerdingen, Germany, Corpus Christi, TX, Castle Hayne, NC). For the Crump et al. (2003) study, grouped observed and expected number of lung cancer mortalities along with cumulative CrVI exposures were used to obtain the maximum likelihood estimate and asymptotic variance of the slope (ß) for the linear multiplicative relative risk model using Poisson regression modeling. For the Gibb et al. (2000) study, Cox proportional hazards modeling was performed with optimal exposure lag and adjusting for the effect of covariates (e.g., smoking) to estimate ß values. Life-table analyses were used to develop URFs for each of the two key studies, as well as for supporting and related studies. The two key study URFs were combined using weighting factors relevant to confidence to derive the final URF for CrVI of 2.3E-03 per µgCrVI/m(3).

Quantitative risk assessment of exposures to butadiene in EU occupational settings based on the University of Alabama at Birmingham epidemiological study.

The excess risks due to 1,3-butadiene (BD) inhalation in EU occupational settings are quantified for leukemia, AML, CLL, CML, lymphoid neoplasms, and myeloid neoplasms. The most recent data from the University of Alabama at Birmingham epidemiological study of North American workers in the styrene-butadiene rubber industry are modeled. The number of high-intensity tasks (HITs) and other exposure covariates may be more important predictors than cumulative BD ppm-years alone. For example, all of the 71 leukemia decedents in the UAB study who were exposed to BD had some BD HITs. None of the 1192 exposed workers without BD HITs had leukemia mortalities. The authors' best estimate (consolidated over all endpoints) of the average occupational BD exposure concentration for 45 years of exposure starting at age 20 corresponding to an added risk of 1/10,000 by age 70 is 7.2 ppm. Cumulative BD ppm-years is not statistically significantly associated with CML, AML, or myeloid neoplasms or (after any one of eight exposure covariates is included in the modeling) leukemia. The statistical significance of the slopes for leukemia, CLL, and lymphoid neoplasms unadjusted for covariate effects disappears when modeling is restricted to person years with less than 200 cumulative BD ppm-years.

Misinterpretation of categorical rate ratios and inappropriate exposure-response model fitting can lead to biased estimates of risk: ethylene oxide case study.

There are pitfalls associated with exposure-response modeling of human epidemiological data based on rate ratios (RRs). Exposure-response modeling is best based on individual data, when available, rather than being based on summary results of that data such as categorical RRs. Because the data for the controls (or the lowest exposure interval if there are not enough controls) are random and not known with certainty a priori, any exposure-response model fit to RRs should estimate the intercept rather than fixing it equal to one. Evaluation of a model's goodness-of-fit to the individual data should not be based on the assumption that summary RRs describe the true underlying exposure-response relationship. These pitfalls are illustrated by Monte Carlo simulation examples with known underlying models. That these pitfalls are a practical concern is illustrated by the need for U.S. EPA to reconsider its most recent evaluation of ethylene oxide. If they had avoided these pitfalls, their exposure-response modeling would have been in better agreement with the log-linear model fit to the individual data.

Development of a cancer-based chronic inhalation reference value for hexavalent chromium based on a nonlinear-threshold carcinogenic assessment.

The carcinogenicity of hexavalent chromium(CrVI) is of significant interest to regulatory agencies for the protection of public health and to industry. Additionally, the mode of action (MOA) and conditions under which CrVI may induce carcinogenicity (e.g., reductive capacity considerations) have recently been the subject of significant scientific debate. Epidemiological data supported by data relevant to the carcinogenic MOA support considering nonlinear-threshold carcinogenic assessments for comparison to default linear low-dose extrapolation approaches. This study reviews epidemiological studies available in the scientific literature and conducts additional statistical dose-response analyses to identify potential carcinogenic thresholds and points of departure (PODs) in the context of supportive MOA information for a nonlinear-threshold inhalation carcinogenic assessment. Dosimetric adjustments and application of appropriate uncertainty factors (total UF of 30) to the selected cumulative exposure POD results in a cancer-based chronic inhalation reference value (ReV) of 0.24 µgCrVI/m(3). This chronic ReV is 300 times higher than the 1 in 100,000 excess cancer risk air concentration of 8E-04 µg/m(3) based on USEPA's unit risk factor.

Development of a unit risk factor for nickel and inorganic nickel compounds based on an updated carcinogenic toxicity assessment.

The TCEQ has developed a URF for nickel based on excess lung cancer in two epidemiological studies of nickel refinery workers with nickel species exposure profiles most similar to emissions expected in Texas (i.e., low in sulfidic nickel). One of the studies (Enterline and Marsh, 1982) was used in the 1986 USEPA assessment, while the other (Grimsrud et al., 2003) is an update to an earlier study (Magnus et al., 1982) used by USEPA. The linear multiplicative relative risk model with Poisson regression modeling was used to obtain maximum likelihood estimates and asymptotic variances for cancer potency factors (ß) using cumulative nickel exposure levels versus observed and expected lung cancer mortality (Enterline and Marsh, 1982) or lung cancer incidence cases (Grimsrud et al., 2003). Life-table analyses were then used to develop URFs from these two studies, which were combined using weighting factors relevant to confidence to derive the final URF for nickel of 1.7E-04 per µg/m³. The de minimis air concentration corresponding to a 1 in 100,000 extra lung cancer risk level is 0.059 µg/m³. The TCEQ will use this conservative value to protect the general public in Texas against the potential carcinogenic effects from chronic exposure to nickel.

An updated inhalation unit risk factor for arsenic and inorganic arsenic compounds based on a combined analysis of epidemiology studies.

The United States Environmental Protection Agency (USEPA) developed an inhalation unit risk factor (URF) of 4.3E-03 per µg/m(3) for arsenic in 1984 for excess lung cancer mortality based on epidemiological studies of workers at two smelters: the Asarco smelter in Tacoma, Washington and the Anaconda smelter in Montana. Since the USEPA assessment, new studies have been published and exposure estimates were updated at the Asarco and Anaconda smelters and additional years of follow-up evaluated. The Texas Commission on Environmental Quality (TCEQ) has developed an inhalation URF for lung cancer mortality from exposures to arsenic and inorganic arsenic compounds based on a newer epidemiology study of Swedish workers and the updates of the Asarco and Anaconda epidemiology studies. Using a combined analysis approach, the TCEQ weighted the individual URFs from these three epidemiology cohort studies, to calculate a final inhalation URF of 1.5E-04 per µg/m(3). In addition, the TCEQ also conducted a sensitivity analysis, in which they calculated a URF based on a type of meta-analysis, and these results compared well with the results of the combined analysis. The no significant concentration level (i.e., air concentration at 1 in 100,000 excess lung cancer mortality) is 0.067µg/m(3). This value will be used to evaluate ambient air monitoring data so the general public in Texas is protected against adverse health effects from chronic exposure to arsenic.

Quantitative cancer risk assessment for ethylene oxide inhalation in occupational settings.

The estimated occupational ethylene oxide (EO) exposure concentrations corresponding to specified extra risks are calculated for lymphoid mortality as the most appropriate endpoint, despite the lack of a statistically significant exposure-response relationship. These estimated concentrations are for occupational exposures--40 years of occupational inhalation exposure to EO from age 20 to age 60 years. The estimated occupational inhalation exposure concentrations (ppm) corresponding to specified extra risks of lymphoid mortality to age 70 years in a population of male and female EO workers are based on Cox proportional hazards models of the most recent updated epidemiology cohort mortality studies of EO workers and a standard life-table calculation. An occupational exposure at an inhalation concentration of 2.77 ppm EO is estimated to result in an extra risk of lymphoid mortality of 4 in 10,000 (0.0004) in the combined worker population of men and women from the two studies. The corresponding estimated concentration decreases slightly to 2.27 ppm when based on only the men in the updated cohorts combined. The difference in these estimates reflects the difference between combining all of the available data or focusing on only the men and excluding the women who did not show an increase in lymphoid mortality with EO inhalation exposure. The results of sensitivity analyses using other mortality endpoints (all lymphohematopoietic tissue cancers, leukemia) support the choice of lymphoid tumor mortality for estimation of extra risk.

Butadiene cancer exposure-response modeling: based on workers in the styrene-butadiene-rubber industry: total leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.

Cox regression is used to estimate exposure-response models (with cumulative 1,3-butadiene (BD) ppm-years as the exposure metric) based on the most recent data and validated exposure estimates from UAB's study of North American workers in the styrene-butadiene-rubber industry. These data are substantially updated from those in USEPA's 2002 risk assessment. The slope for cumulative BD ppm-years is not statistically significantly different than zero for CML, AML, or, when any one of eight exposure covariates is added to the model, for all leukemias combined (total leukemia). For total leukemia, the EC(1/100,000) is approximately 0.15 BD environmental ppm and the corresponding unit risk factor is approximately 0.00007 per BD environmental ppm. The excess risk for CML is approximately 15-fold less than for total leukemia. The maximum likelihood estimates suggest that there is no excess risk for AML from cumulative BD ppm-years. For CLL, the slope is statistically significantly different than zero. The excess risk for CLL is approximately 2.5-fold less than for total leukemia. For both total leukemia and CLL, the slope is not statistically significantly different than zero when the exposure-response modeling is based on the person-years with cumulative BD ppm-years less than or equal to 300 ppm-years.

Quantitative cancer risk assessment based on NIOSH and UCC epidemiological data for workers exposed to ethylene oxide.

The most recent epidemiological data on individual workers in the NIOSH and updated UCC occupational studies have been used to characterize the potential excess cancer risks of environmental exposure to ethylene oxide (EO). In addition to refined analyses of the separate cohorts, power has been increased by analyzing the combined cohorts. In previous SMR analyses of the separate studies and the present analyses of the updated and pooled studies of over 19,000 workers, none of the SMRs for any combination of the 12 cancer endpoints and six sub-cohorts analyzed were statistically significantly greater than one including the ones of greatest previous interest: leukemia, lymphohematopoietic tissue, lymphoid tumors, NHL, and breast cancer. In our study, no evidence of a positive cumulative exposure-response relationship was found. Fitted Cox proportional hazards models with cumulative EO exposure do not have statistically significant positive slopes. The lack of increasing trends was corroborated by categorical analyses. Cox model estimates of the concentrations corresponding to a 1-in-a-million extra environmental cancer risk are all greater than approximately 1ppb and are more than 1500-fold greater than the 0.4ppt estimate in the 2006 EPA draft IRIS risk assessment. The reasons for this difference are identified and discussed.

Life-table calculations of excess risk for incidence versus mortality: ethylene oxide case study.

In US EPA's evaluation of ethylene oxide (EO) in 2006, the calculation of the excess risk of lymphohematopoietic (LH) cancer incidence was flawed. The calculation was inappropriately based on an exposure-response model for LH mortality instead of LH incidence. This is especially inappropriate for EO because EO exposure may not increase LH incidence except at high doses. The observed increases in LH mortality with EO exposure in males in the NIOSH epidemiology study, although not statistically significant, can be explained at all but the highest doses by exposure-dependent changes in the survival time between LH onset and LH mortality without any changes in LH incidence. Furthermore, EPA's life-table calculations of excess risk of incidence used formulas that are only appropriate for mortality. All of these concerns strongly suggest that EPA should limit their excess risk calculations to mortality unless they have data from an epidemiology study of incidence from which to derive an exposure-response model. What excess risks are calculated and how they are calculated is important for a scientifically-defensible regulatory assessment of EO and other substances.

Reevaluation of Historical Exposures to Ethylene Oxide Among U.S. Sterilization Workers in the National Institute of Occupational Safety and Health (NIOSH) Study Cohort.

The 2016 U.S. Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) assessment for ethylene oxide (EO) estimated a 10-6 increased inhalation cancer risk of 0.1 parts per trillion, based on National Institute of Occupational Safety and Health (NIOSH) epidemiology studies of sterilization facility workers exposed to EO between 1938 and 1986. The worker exposure estimates were based on a NIOSH statistical regression (NSR) model "validated" with EO levels measured after 1978. Between 1938 and 1978, when EO data was unavailable, the NSR model predicts exposures lowest in 1938 increasing to peak levels in 1978. That increasing EO concentration trend arose, in part, because engineering/industrial-hygiene (E/IH) factors associated with evolving EO-sterilization equipment and operations before 1978 were not properly considered in the NSR model. To test the NSR model trend prediction, a new E/IH-based model was developed using historical data on EO kill concentrations, EO residue levels in sterilized materials, post-wash EO concentrations in a sterilization chamber, and information on facility characteristics and sterilizer operator practices from operators familiar with pre-1978 industry conditions. The E/IH 90th percentile of 8 h time-weighted average EO exposures (C90) for highly exposed sterilizer operators was calibrated to match 1978 C90 values from the NSR model. E/IH model C90 exposures were estimated to decrease over time from levels 16 and were four-fold greater than NSR-estimated exposures for workers during 1938-1954 and 1955-1964. This E/IH modeled trend is opposite to that of NSR model predictions of exposures before 1978, suggesting that EPA's exclusive reliance on the NIOSH cohort to estimate EO cancer risk should be re-examined.

Cancer risk assessment for 1,3-butadiene: dose-response modeling from an epidemiological perspective.

The dose-response assessment of the association between 1,3-butadiene (BD) and leukemia mortality among workers in the North American synthetic rubber industry is explored. Analyses are based on the most recent University of Alabama at Birmingham epidemiological study and exposure estimation. The U.S. EPA Science Advisory Board recommendations of using the most recent data and giving consideration to peak exposures to BD have been followed. If cumulative BD ppm-years is to be used as the predictor of the leukemia rate ratio, then the performance of that predictor is statistically significantly improved if the slope in the predictor is estimated with age and the cumulative number of BD peaks (where a BD peak is any exposure, regardless of duration, to a BD concentration above 100 ppm) added as categorical covariates. After age and the cumulative number of BD peaks are incorporated as categorical covariates in the Poisson regression model, the estimated concentration (EC(001)) corresponding to an excess risk of 0.001 as a result of continuous environmental exposure is 11.2 ppm; however, the estimated slope for BD cumulative ppm-years in the linear rate ratio for leukemia used to derive this EC(001) is not statistically significantly different from zero. Sensitivity analyses using alternative models indicate either essentially no risk or estimated EC(001) values of 9 and 77 ppm. Analyses suggesting the absence of a statistically significant low-dose risk versus cumulative BD ppm-years are presented. Sensitivity analyses of other malignant neoplasms of lymphatic and hematopoietic tissue (specifically, lymphoid and myeloid neoplasms) resulted in conclusions about the dose-response modeling methodology that were supportive of the methodology used for leukemia.

PBPK-Based Probabilistic Risk Assessment for Total Chlorotriazines in Drinking Water.

The risk of human exposure to total chlorotriazines (TCT) in drinking water was evaluated using a physiologically based pharmacokinetic (PBPK) model. Daily TCT (atrazine, deethylatrazine, deisopropylatrazine, and diaminochlorotriazine) chemographs were constructed for 17 frequently monitored community water systems (CWSs) using linear interpolation and Krieg estimates between observed TCT values. Synthetic chemographs were created using a conservative bias factor of 3 to generate intervening peaks between measured values. Drinking water consumption records from 24-h diaries were used to calculate daily exposure. Plasma TCT concentrations were updated every 30 minutes using the PBPK model output for each simulated calendar year from 2006 to 2010. Margins of exposure (MOEs) were calculated (MOE = [Human Plasma TCTPOD] ÷ [Human Plasma TCTEXP]) based on the toxicological point of departure (POD) and the drinking water-derived exposure to TCT. MOEs were determined based on 1, 2, 3, 4, 7, 14, 28, or 90 days of rolling average exposures and plasma TCT Cmax, or the area under the curve (AUC). Distributions of MOE were determined and the 99.9th percentile was used for risk assessment. MOEs for all 17 CWSs were >1000 at the 99.9(th)percentile. The 99.9(th)percentile of the MOE distribution was 2.8-fold less when the 3-fold synthetic chemograph bias factor was used. MOEs were insensitive to interpolation method, the consumer's age, the water consumption database used and the duration of time over which the rolling average plasma TCT was calculated, for up to 90 days. MOEs were sensitive to factors that modified the toxicological, or hyphenated appropriately no-observed-effects level (NOEL), including rat strain, endpoint used, method of calculating the NOEL, and the pharmacokinetics of elimination, as well as the magnitude of exposure (CWS, calendar year, and use of bias factors).

Statistical inferences about the mechanism of action in carcinogenicity studies.

An innovative approach to dose-response modeling provides statistical insight into the relative likelihood of different mechanisms of action in cancer dose-response studies. Two illustrative examples are given based on time-to-tumor data on mammary fibroadenoma and adenocarcinoma in female Sprague-Dawley rats using 34 different dose metrics. The likelihood for the study outcome was calculated for each dose metric and compared with the background likelihood using a likelihood-ratio test. In the first example, fibroadenomas were strongly related to the presence or absence of mammary secretory activity, galactoceles, pituitary tumors, and abnormal diestrous days in weeks 1 to 26. Adenocarcinomas were the most strongly related to the number and percentage of abnormal estrous days. In these examples, the usual dose metric based on the dietary concentration of the pesticide had some explanatory ability but not nearly as much as the dose metrics more directly related to hormonal mechanisms of action.

A comprehensive review of occupational and general population cancer risk: 1,3-Butadiene exposure-response modeling for all leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, myeloid neoplasm and lymphoid neoplasm.

Excess cancer risks associated with 1,3-butadiene (BD) inhalation exposures are calculated using an extensive data set developed by the University of Alabama at Birmingham (UAB) from an epidemiology study of North American workers in the styrene butadiene rubber (SBR) industry. While the UAB study followed SBR workers, risk calculations can be adapted to estimate both occupational and general population risks. The data from the UAB SBR study offer an opportunity to quantitatively evaluate the association between cumulative exposure to BD and different types of cancer, accounting for the number of tasks involving high-intensity exposures to BD as well as confounding associated with the exposures to the multiple other chemicals in the SBR industry. Quantitative associations of BD exposure and cancer, specifically leukemia, can be further characterized by leukemia type, including potential associations with acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML), and the groups of lymphoid and myeloid neoplasms. Collectively, these multiple evaluations lead to a comprehensive analysis that makes use of all of the available information and is consistent with the risk assessment goals of the USEPA and other regulatory agencies, and in line with the recommendations of the USEPA Science Advisory Board. While a range of cancer risk values can result from these multiple factors, a preferred case for occupational and general population risk is highlighted. Cox proportional hazards models are used to fit exposure-response models to the most recent UAB data. The slope of the model with cumulative BD ppm-years as the predictor variable is not statistically significantly greater than zero for CML, AML, or, when any one of eight exposure covariates is added to the model, for all leukemias combined. The slope for CLL is statistically significantly different from zero. The slope for myeloid neoplasms is not statistically significantly greater than zero while the slope for lymphoid neoplasms is statistically significantly greater than zero. The excess risk for the general population is largest for lymphoid neoplasms. The best estimates of the environmental concentrations (ECs) associated with an excess risk of 1/100,000 by age 70 years for lymphoid neoplasms, all leukemias, and CLL are EC(1/100,000)'s equal to 0.06, 0.16 and 0.38 ppm, respectively. The best estimates of the occupational BD exposure from 20 to 65 years of age associated with an excess risk of 1/10,000 by age 70 years for lymphoid neoplasms, all leukemias, and CLL are the EC(1/10,000)'s of 2.7, 7.3 and 15.1 ppm, respectively.

Consideration of rat chronic progressive nephropathy in regulatory evaluations for carcinogenicity.

Chronic progressive nephropathy (CPN) is a spontaneous renal disease of rats which can be a serious confounder in toxicology studies. It is a progressive disease with known physiological factors that modify disease progression, such as high dietary protein. The weight of evidence supports an absence of a renal counterpart in humans. There is extensive evidence that advanced CPN, particularly end-stage kidney, is a risk factor for development of a background incidence of atypical tubule hyperplasia and renal tubule tumors (RTT). The likely cause underlying this association with tubule neoplasia is the long-term increased tubule cell proliferation that occurs throughout CPN progression. As a variety of chemicals are able to exacerbate CPN, there is a potential for those exacerbating the severity up to and including end-stage kidney to cause a marginal increase in RTT and their precursor lesions. Extensive statistical analysis of National Toxicology Program studies shows a strong correlation between high-grade CPN, especially end-stage CPN, and renal tumor development. CPN as a mode of action (MOA) for rat RTT has received attention from regulatory authorities only recently. In the absence of toxic effects elsewhere, this does not constitute a carcinogenic effect of the chemical but can be addressed through a proposed MOA approach for regulatory purposes to reach a decision that RTT, developing as a result of CPN exacerbation in rats, have no relevance for human risk assessment. Guidelines are proposed for evaluation of exacerbation of CPN and RTT as a valid MOA for a given chemical.

Statistical Comparison of Carcinogenic Effects and Dose-Response Relationships in Rats and Mice for 2,4-Toluene Diamine to those Ascribed to Toluene Diisocyanate.

The U.S. National Toxicology Program (NTP) conducted 2-year bioassays of commercial grade toluene diisocyanate (TDI) (80% 2,4-TDI and 20% 2,6-TDI) and 2,4-toluene diamine (TDA) and concluded that both were carcinogenic in rodents. In the TDI study, there was an unproven but likely formation of TDA either because of flawed test-substance handling and storage conditions and/or the atypical exposure conditions employed. Although the carcinogenic responses in both studies were qualitatively similar, several statistical analyses were performed to substantiate this possibility more rigorously. Seven different statistical approaches combine to yield a robust and consistent conclusion that, if only a small fraction (approximately 5%) of the dose of TDI were hydrolyzed to TDA in the TDI study, then that would be sufficient to explain the observed carcinogenic responses in the TDI study.