Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

LEAD

Summary of PDE for Lead

Lead (Pb)

Oral

Parenteral

Inhalation

PDE (µg/day)

5.0

5.0

5.0

Introduction

Lead (Pb) occurs in organic and inorganic forms. The generally bivalent lead compounds include water-soluble salts such as lead acetate as well as insoluble salts such as lead oxides. Organic lead compounds include the gasoline additives tetramethyl- and tetraethyl-lead. Organic lead compounds undergo fairly rapid degradation in the atmosphere and form persistent inorganic lead compounds in water and soil. Lead has no known biological function in human or mammalian organisms (ATSDR, 2007). In humans and animals, exposure to lead may cause neurological, reproductive, developmental, immune, cardiovascular and renal health effects. In general, sensitivity to lead toxicity is greater when there is exposure in utero and in children compared to adults. A target blood level of 1-2 µg/dL was set, and using modelling programs (US EPA, 2009) that assumed 100% bioavailability and no other exposure, a PDE was obtained. For this reason, the PDEs are the same regardless of the route of administration. Safety Limiting Toxicity Adverse neurobehavioral effects are considered to be the most sensitive and most relevant endpoint in humans after oral exposure. Data from epidemiological studies show that blood lead levels <5 µg/dL may be associated with neurobehavioral deficits in children (NTP, 2011). According to the US EPA model (Integrated Exposure Uptake Biokinetic (IEUBK) Model, 1994) (100% absorption, no other sources of lead), oral intake of 5 µg/day translates into a blood level of 1-2 µg/dL for children age 0-7 years (0-82 months) (US EPA, 2007, 2009). PDE – Oral Exposure

PDE = 5.0 µg/day

PDE – Parenteral Exposure

The oral effects of Pb are based on blood levels. Therefore, the parenteral PDE is equal to the oral PDE.

PDE = 5.0 µg/day

PDE – Inhalation Exposure

The oral effects of Pb are based on blood levels. Therefore, the inhalation PDE is equal to the oral PDE.

PDE = 5.0 µg/day

R EFERENCES

ATSDR. Toxicological profile for lead. Agency for Toxic Substances and Disease Registry, Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA.

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