Effects of Exposure Imprecision on Estimation of the Benchmark Dose

In regression analysis failure to adjust for imprecision in the exposure variable is likely to lead to underestimation of the exposure effect. However, the consequences of exposure error for determination of safe doses of toxic substances have so far not received much attention. The benchmark approach is one of the most widely used methods for development of exposure limits. An important advantage of this approach is that it can be applied to observational data. However, in this type of data, exposure markers are seldom measured without error. It is shown that, if the exposure error is ignored, then the benchmark approach produces results that are biased toward higher and less protective levels. It is therefore important to take exposure measurement error into account when calculating benchmark doses. Methods that allow this adjustment are described and illustrated in data from an epidemiological study on the health effects of prenatal mercury exposure.     

Estimation of a Benchmark Dose in the Presence or Absence of Hormesis Using Posterior Averaging

U.S. Environment Protection Agency benchmark doses for dichotomous cancer responses are often estimated using a multistage model based on a monotonic dose‐response assumption. To account for model uncertainty in the estimation process, several model averaging methods have been proposed for risk assessment. In this article, we extend the usual parameter space in the multistage model for monotonicity to allow for the possibility of a hormetic dose‐response relationship. Bayesian model averaging is used to estimate the benchmark dose and to provide posterior probabilities for monotonicity versus hormesis. Simulation studies show that the newly proposed method provides robust point and interval estimation of a benchmark dose in the presence or absence of hormesis. We also apply the method to two data sets on carcinogenic response of rats to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin.     

Dose-Response Assessment of Airborne Methyl Isothiocyanate (MITC) Following a Metam Sodium Spill

A tank car derailment in northern California in 1991 spilled metam sodium into the Sacramento River, and released its breakdown product, methyl isothiocyanate (MITC), into the air. This paper describes the risk evaluation process used. Over 240 individuals reported symptoms such as eye and throat irritation, dizziness, and shortness of breath. Reference exposure levels (RELs) for 1 hr were developed for MITC and compared to exposure concentrations. Ocular irritation in cats was the most sensitive endpoint reported. The no observed adverse effect level (NOAEL), divided by an uncertainty factor (UF) of 100, produced an REL of 0.5 ppb of MITC in air to prevent discomfort. An REL to prevent disability was estimated to be 40 ppb. An REL to prevent life-threatening injury was estimated to be 150 ppb. Measured MITC levels ranged from 0.2-37 ppb and estimated peak levels ranged from 140-1600 ppb. The usefulness of RELs for emergency planning is discussed.     

Estimation of Benchmark Dose of Lifetime Cadmium Intake for Adverse Renal Effects Using Hybrid Approach in Inhabitants of an Environmentally Exposed River Basin in Japan

The aim of this study is to estimate the reference level of lifetime cadmium intake (LCd) as the benchmark doses (BMDs) and their 95% lower confidence limits (BMDLs) for various renal effects by applying a hybrid approach. The participants comprised 3,013 (1,362 men and 1,651 women) and 278 (129 men and 149 women) inhabitants of the Cd‐polluted and nonpolluted areas, respectively, in the environmentally exposed Kakehashi River basin. Glucose, protein, aminonitrogen, metallothionein, and β₂‐microglobulin in urine were measured as indicators of renal dysfunction. The BMD and BMDL that corresponded to an additional risk of 5% were calculated with background risk at zero exposure set at 5%. The obtained BMDLs of LCd were 3.7 g (glucose), 3.2 g (protein), 3.7 g (aminonitrogen), 1.7 g (metallothionein), and 1.8 g (β₂‐microglobulin) in men and 2.9 g (glucose), 2.5 g (protein), 2.0 g (aminonitrogen), 1.6 g (metallothionein), and 1.3 g (β₂‐microglobulin) in women. The lowest BMDL was 1.7 g (metallothionein) and 1.3 g (β₂‐microglobulin) in men and women, respectively. The lowest BMDL of LCd (1.3 g) was somewhat lower than the representative threshold LCd (2.0 g) calculated in the previous studies. The obtained BMDLs may contribute to further discussion on the health risk assessment of cadmium exposure.