Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

Studies in humans and experimental animals indicate that, when ingested, several selenium compounds including selenite, selenate, and selenomethionine are readily absorbed, often to greater than 80% of the administered dose (ATSDR, 2003). On the basis of oral bioavailability of ~80%, the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 2 (as described in Section 3.1).

PDE = 170 µg/d / 2 = 85 µg/day

PDE – Inhalation Exposure

Respiratory endpoints are the most sensitive markers for inhalation exposure in occupational studies. Occupational limits have established time weighted averages for selenium exposures of 0.2 mg/m 3 (US DoL, 2013) and 0.07 by the European Union Scientific Expert Group (EU SEG, 1992). However, the EU SEG Occupation Exposure Limits (OEL) was based on hydrogen selenide, a form not likely to be present in inhalation products. Thus, using the OEL derived by US DoL, and taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the inhalation PDE is calculated as below.

For continuous dosing = 0.2 mg/m 3 8 hr/d x 5 d/wk = 0.048 mg/m 3 = 0.000048 mg/L 24 hr/d x 7 d/wk 1000 L/m 3

Daily dose =

0.000048 mg/L x 28800 L = 0.027 mg/kg 50 kg

PDE = 0.027 mg/kg x 50 kg / 1 x 10 x 1 x 1 x 1= 0.135 mg/day =135 µg/day

R EFERENCES

ATSDR. Toxicological profile for selenium. Agency for Toxic Substances and Disease Registry, Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2003. EU SEG. Recommendation from the Scientific Expert Group on Occupation Exposure Limits for Hydrogen selenide. European Union Scientific Expert Group. 1992;SEG/SUM/22C IARC. Overall evaluations of carcinogenicity: An update of IARC monographs volumes 1 to 42. Monographs on the Evaluation of the Carcinogenic Risks to Humans. International Agency for Research on Cancer, World Health Organization, Lyon. 1987;Suppl 7. IARC. Some aziridines, N-, S- and O-mustards and selenium. Summary of data reported and evaluation. Monographs on the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer, World Health Organization, Lyon. 1999. NTP. Bioassay of selenium sulfide (gavage) for possible carcinogenicity. National Toxicology Program, US Department of Health and Human Services. 1980;Technical Report Series No 194. US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of Labor. 2013. US EPA. Selenium and compounds (CAS No. 7782-49-2). Integrated Risk Information System (IRIS). 2002. WHO. Selenium in Drinking-water; Background document for development of WHO Guidelines for Drinking-water Quality. World Health Organization, Geneva. 2011. WHO/HSE/WSH/10.01/14

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