Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

SELENIUM

Summary of PDE for Selenium

Selenium (Se)

Oral

Parenteral

Inhalation

PDE (µg/day)

170

85

135

Introduction

Selenium (Se) is present in the earth's crust, often in association with sulfur-containing minerals. It can assume four oxidation states (-2, 0, +4, +6) and occurs in many forms, including elemental selenium, selenites and selenates. Selenium is an essential trace element for many species, including humans. Selenium is incorporated into proteins via a specific selenocysteine tRNA. Selenium is being used as a catalyst in the manufacture of rubber. Ru-Se catalysts are used in oxygen reduction. Aryl- and alkyl-Selenium reagents have various applications in organic synthesis. Selenium was listed as a Group 3 compound (not classifiable for carcinogenesis) by IARC (1987). The only selenium compound that has been shown to be carcinogenic in animals is selenium sulfide (NTP, 1980). According to the US EPA, selenium sulfide is in Group B2 (probable human carcinogen) (US EPA, 2002). Other selenium compounds are classified as D; not classifiable as to carcinogenicity in humans. The most significant toxicity observed with excessive exposure in humans to Se is selenosis, characterized primarily by dermal and neurological effects, including unsteady gait and paralysis (ATSDR, 2003). There is some concern over exposure to excessive levels of selenium in the diet; to limit the total exposure to Se, various organizations have set an upper tolerable limit at 400 µg/day (WHO, 2011). Occupational studies describe respiratory effects such as irritation of the nose, respiratory tract, and lungs, bronchial spasms, and coughing following chronic exposure to selenium dioxide or elemental selenium as dust. Respiratory symptoms similar to those reported for occupationally-exposed humans have been seen in animals inhaling high doses of elemental selenium fumes or dust, and studies of animals with acute inhalation exposure to hydrogen selenide or elemental selenium fumes or dust have reported hepatocellular degeneration and atrophy of the liver. Absorption after inhalation exposure is uncertain (ATSDR, 2003). In a rat carcinogenicity study of selenium sulfide, the NOAEL for hepatocellular carcinoma was 3 mg/kg/day (1.7 mg Se/kg/day) (NTP, 1980). Although, there is insufficient data to assess carcinogenicity of other forms of selenium, and the human relevance of the rodent liver tumors has been questioned (IARC, 1999), this is the best available study. Some human data are available but only in a limited number of subjects (ATSDR, 2003). The calculated PDE is in line with the MRL of 5 µg/kg/day for Se (ATSDR, 2003). Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as below. PDE – Oral Exposure Safety Limiting Toxicity

PDE = 1.7 mg/kg/d x 50 kg / 5 x 10 x 1 x 10 x 1 = 170 µg/day

A factor of 10 was chosen for F4 because of the risk of selenosis.

PDE – Parenteral Exposure

66