Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

PDE – Oral Exposure

The oral PDE is based on the chronic effects of arsenic to skin and sets the limit at 15 µg/day based on Agency for Toxic Substances and Disease Registry (ATSDR) MRL and US EPA limit of 0.0003 mg/kg/day (ATSDR, 2007; US EPA 2007; EU EFSA, 2009). The PDE calculated based on the ATSDR MRL is consistent with drinking water standards (WHO, 2011).

PDE = 0.0003 mg/kg/d x 50 kg = 0.015 mg/d = 15 µg/day

No modifying factors were applied because they are incorporated into the derivation of the MRL.

PDE – Parenteral Exposure

The oral bioavailability of arsenic is ~95%. The most direct evidence is from a study that evaluated the 6-day elimination of arsenic in healthy humans who were given water from a high-arsenic sampling site (arsenic species not specified) and that reported approximately 95% absorption (Zheng et al. , 2002). Therefore the PDE is identical to the oral PDE.

PDE = 15 µg/day

PDE – Inhalation Exposure

Increased risk of lung cancer and other respiratory disorders have been reported following inhalation exposure to workers in the occupational setting. The rationale for using a cancer endpoint for inhalation to set the PDE is the relative lack of information on linear-dose extrapolation, as compared to the oral route. No modifying factors are needed as the URF were determined for the protection of the general public. Based on the assessment conducted by Erraguntla et al. (2012), based on the risk of 1:100.000, the inhalation PDE is:

PDE = 0.067 µg/m 3 / 1000 L/m 3 x 28800 L/d = 1.9 µg/day

No modifying factors were applied because the PDE is based on a URF derived from the multiplicate relative risk model described by Erraguntla et al. (2012).

R EFERENCES

Ahsan H, Steinmaus C. Invited commentary: use of arsenical skin lesions to predict risk of internal cancer-implications for prevention and future research. Am J Epidemiol 2013;177:213-6. ATSDR. Toxicological profile for arsenic. Agency for Toxic Substances and Disease Registry, Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2007. Chen CJ, Hsu LI, Wang CH, Shih WL, Hsu YH, Tseng MP et al. Biomarkers of exposure, effect, and susceptibility of arsenic-induced health hazards in Taiwan. Toxicol Appl Pharmacol 2005;206:198- 206. Chu HA, Crawford-Brown DJ. Inorganic arsenic in drinking water and bladder cancer: a metaanalysis for dose-response assessment. Int J Environ Res Public Health 2006;3:316- 22. Chu HA, Crawford-Brown DJ. Inorganic arsenic in drinking water and bladder cancer: a metaanalysis for dose-response assessment. Int J Environ Res Public Health 2007;4:340-

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