ARSENIC

Comments:

INORGANIC ARSENIC (iAs): No new human studies were identified by JECFA that would alter the previous assessment that iAs causes cancer (lung, bladder and skin); in fact, the evidence base for cancer has been strengthened. Several new studies have also strengthened the evidence base for the association between arsenic exposure and ischemic heart disease (IHD). JECFA therefore conducted dose–response analyses for both cancer and IHD. JECFA noted that the dose–response modelling of the three key human studies on IHD produced values for the benchmark dose lower confidence interval for a 0.5% increased incidence (BMDL0.5) that were similar (range, 0.30–0.34 μg/kg bw per day). JECFA therefore selected a BMDL0.5 of 0.3 g/kg bw per day for IHD as a POD. JECFA noted that the POD for IHD of 0.3 μg/kg bw per day is lower than the lowest benchmark dose lower confidence interval for a 0.1% increased incidence (BMDL0.1) for cancer (lung) of 1 μg/kg bw per day; it therefore provides a comparable level of protection for cancer at a benchmark response (BMR) of less than 0.1% and for IHD at a BMR of 0.5%. DIMETHYLARSINATE (DMAV): There were no relevant human data for establishing a health-based guidance value (HBGV) for exposure to DMAV. Following dose–response analysis of the key outcomes identified from the critical study in rats, a POD of 0.74 mg/kg bw per day was selected based on urinary bladder hyperplasia in female rats exposed for 104 weeks to DMAV. JECFA determined that a composite uncertainty factor of 125 was suitable to address uncertainties that were identified. This composite uncertainty factor comprises a default factor of 10- fold for intra-species differences in toxicodynamics and toxicokinetics and a 2.5-fold default factor for inter-species differences in toxicodynamics. JECFA determined that an uncertainty factor of 1 for interspecies differences in toxicokinetics is sufficient, as rats are expected to metabolize and retain more DMAV compared with humans, resulting in a greater sensitivity to the adverse effects of oral exposure to DMAV . An additional 5-fold factor for database uncertainty (e.g. clinical relevance for non-apical outcomes in the urinary bladder at lower doses compared with histopathological lesions, and additional uncertainty concerning the potential for heightened sensitivity of young animals) was included, which is within the range (2–10) suggested in Environmental Health Criteria (EHC) 240: Principles and Methods for the Risk Assessment of Chemicals in Food. Accordingly, JECFA established a non-neoplastic HBGV of 6 µg/kg bw per day (rounded from 5.9 µg/kg bw per day). METHYLARSONATE (MMAV ): There were no relevant human data for establishing an HBGV for exposure to MMAV . Following dose–response analysis of the key outcomes identified from the critical study in mice, a POD of 0.53 mg/kg bw per day was selected based on glomerular nephropathy in male mice exposed for 104 weeks to MMAV . The toxicological database was considered sufficiently robust, meaning that JECFA decided that a default uncertainty factor of 100 was appropriate to address uncertainties identified in the evaluation (i.e. 10-fold for intra- and 10-fold for inter-species differences). Accordingly, JECFA established an HBGV of 5 µg/kg bw per day (rounded from 5.3 µg/kg bw per day).

Intake:

INORGANIC ARSENIC (iAs): In areas where contamination of drinking-water with iAs is expected to be low (< 10 μg/L total arsenic [tAs]), the estimates of mean dietary iAs exposure in children and adults, excluding high seaweed consumers, ranged from less than 0.05 to 0.8 μg/kg bw per day, and P95 estimates ranged from 0.08 to 1.2 μg/kg bw per day. For high seaweed consumers, mean dietary exposures ranged from 0.2 to 3.8 μg/kg bw per day. JECFA noted that the upper end of the ranges for both mean and P95 estimates of dietary exposure exceed the identified POD of 0.3 μg/kg bw per day by at least 2.5-fold. The mean iAs dietary exposure estimates for populations in areas in which drinking-water is contaminated (> 10 μg/L tAs) ranged from 0.4 to 52.5 g/kg bw per day. P95 values ranged from 2.8 to 131.3 μg/kg bw per day. JECFA noted that there is high uncertainty in the P95 values. The upper end of the mean exposure value is 175-fold higher than the identified POD. In areas in which the water supply is highly contaminated with iAs, adverse health effects are well established and have been prevalent. In areas where the water supply is not highly contaminated, JECFA concluded that there is a potential for human health concerns in both children and adults at mean dietary exposures. DIMETHYLARSINATE (DMAV): Since JECFA expressed some uncertainty concerning the adversity of the sporadic incidence of urinary bladder tumours in treated male rats below the stated no-observed-adverseeffects limit (NOAEL) of the authors of the critical study, and considering the proximity of the neoplastic POD (1.03 mg/kg bw per day) to the non-neoplastic POD (0.74 mg/kg bw per day), JECFA considered an additional approach to risk characterization, that is, calculating margins of exposure (MOE) using the neoplastic POD to evaluate the level of concern associated with carcinogenesis at the estimated dietary exposures. JECFA calculated MOEs ranging from 6400 to more than 100 000 for mean dietary exposures (range, < 0.01 to 0.16 µg/kg bw per day; oxidation state not specified and across different cohorts) and from 2100 to more than 50 000 for P95 dietary exposures (range, 0.02 to 0.48 µg/kg bw per day; oxidation state not specified and across different cohorts). JECFA concluded that these MOEs were adequate to address the uncertainties previously mentioned and, given the likely mode of action (non-DNA-reactive mechanism) and the conservatism in some of the assumptions in estimating high level exposures, concluded that, with respect to cancer, dietary exposure to DMAV is unlikely to be of concern to human health. JECFA noted that the dietary exposure estimates for the general population (mean range, < 0.01 to 0.16 µg/kg bw per day; P95 range, 0.02 to 0.48 µg/kg bw per day; oxidation state not specified and across different cohorts) for DMA are below the HBGV. Overall, JECFA concluded that dietary exposure to DMAV is unlikely to be of concern to human health. However, JECFA also noted that a proportion of the DMA dietary exposure may come from DMAIII, which may be more hazardous. METHYLARSONATE: JECFA noted that the mean dietary exposure estimates (range, < 0.01 to 0.03 µg/kg bw per day; oxidation state not specified and across different cohorts) for MMA are below the HBGV. Although a P95 dietary exposure estimate was not available to JECFA for MMA, it was considered reasonable to assume that the P95 for MMA is likely to be approximately 2.5-fold the UB mean (i.e. ~0.08 µg/kg bw per day), which is below the HBGV. Overall, JECFA concluded that dietary exposure to MMAV is unlikely to be of concern. However, JECFA also noted that a proportion of the MMA dietary exposure may come from MMAIII, which may be more hazardous

Meeting:

101

Comments:

Based on data from an epidemiology study conducted on a highly-exposed population, the inorganic arsenic lower limit on the benchmark dose for a 0.5% increased incidence of lung cancer was calculated to be 3 μg/kg bw per day (range: 2–7 μg/kg bw per day) using a range of assumptions to estimate total dietary exposure of the study population to inorganic arsenic from drinking water and food. The Committee concluded that the current PTWI for As (2.1 μg/kg bw per day) was no longer health protective as the BMDL0.5 value was in the same range as the PTWI value. The PTWI for inorganic As has been withdrawn.

Tolerable Intake:

PTWI withdrawn

Meeting:

72

Report: 

Tox Monograph: 

Tolerable Intake:

PTWI 0.015 mg/kg bw

Meeting:

33

Report: 

Tox Monograph: 

Previous Years: