Other toxic effects of lead compounds

The toxicity of lead compounds to humans has been extensively studied. For the last 100 years, considerable attention has been focused on the neurotoxic effects of lead

compounds in young children, following reports of the exposure of children to lead-based house paint. Because of the very large amount of published literature on lead toxicity, this section will provide only a brief review, with references to major reviews and

government documents.

Human exposure to lead is regulated in the occupational and non-occupational

environments (see Section 2.9 and Appendix A for lists of lead regulations). Several end points of concern have been associated with human exposure to lead and lead

compounds; end points identified in adults, children, and/or fetuses include (but are not limited to) neurotoxicity, nephrotoxicity, hematoxicity and anemia, reproductive toxicity, developmental toxicity, and cardiovascular toxicity. The end points are discussed briefly below.

6.2.1 Neurotoxicity

By the 1930s, it was increasingly recognized that exposure to lead compounds (inorganic, lead carbonate based, and lead chromate and oxide pigments) was a frequent cause of encephalopathy in children. Under conditions of chronic exposure, the neurotoxic effects of exposure to lead in paint included loss of speech, seizures, and coma (McKhann 1932). Children who survived these severe events frequently were retarded intellectually and in their motor skills (Silbergeld 1997). Reviews of several large prospective studies of children’s neurocognitive and behavioral development reached a consistent conclusion that “subencephalopathic” exposures to inorganic lead, i.e., at doses associated with blood lead levels as low as 10 μg/dL, are significantly associated with poor outcomes in neurocognitive and behavioral development and with impairments in attention, hearing, and school attainment (ATSDR 1999, Silbergeld 1997).

Although the CNS toxicity of lead in children became the critical end point in pediatrics, inorganic lead compounds also can affect both CNS and peripheral nervous system (PNS) function in adults. Neurotoxic manifestations depend on both dose and duration of

exposure. High levels of exposure cause disabling impairments in PNS function, described as “painter’s wrist” or “foot drop” in the 18th and 19th centuries, as well as profound mental changes and cognitive impairments, which were observed in workers in lead industries in the 19th century. In the 1920s, when production of TEL began in the United States, cases of acute psychosis and hallucinations in workers were reported. Some recent reviews (Stewart et al. 2002, Kamel et al. 2002) have suggested that adult lead exposure may be associated with increased risks of neurodegenerative disease in aging, specifically, amyotrophic lateral sclerosis and dementias.

6.2.2 Nephrotoxicity

The renal toxicity of lead has been well described for over 100 years. Acute

nephrotoxicity has been described in lead-intoxicated children (Loghman-Adham 1997). The evidence in both humans and experimental animals indicates that thresholds exist for lead nephropathy. In rodents, proximal tubular injury occurs at blood lead levels of 60 µg/dL. Observations in humans indicate that blood lead levels greater than 60 µg/dL for up to 12 years are required for nephropathy. Increased risk of end-stage renal failure has been reported in lead workers long after cessation of exposure.

6.2.3 Hematoxicity and anemia

Lead inhibits the biosynthesis of heme through highly specific interactions with one of the rate-limiting enzymes in this pathway, ALAD. As a consequence of this effect, levels of some heme precursors are elevated (by feedback deregulation), and heme levels are decreased (Silbergeld 1987). These effects have been widely used as biomarkers for lead exposure, but they also represent toxic effects of lead and may play a role in target organ responses. Inhibition of heme production, along with toxic effects on globin synthesis and erythrocyte integrity, is associated with anemia at high levels of exposure (> 40 μg/dL).

6.2.4 Reproductive toxicity

Lead is toxic to sperm and can alter endocrine function in adults. Decreases in

spermatologic parameters were reported in men exposed to inorganic lead compounds in battery plants and were associated with blood lead levels as low as 40 μg/dL, which are well within current occupational standards; in some cases, these deficits were ameliorated when lead exposure and blood lead levels were reduced (Sallmen 2001). No specific effects of lead have been reported on female reproduction; however, lead is toxic to fetal development, and these effects sometimes are misinterpreted as effects on pregnant women or women of childbearing age.

6.2.5 Developmental toxicity

Lead crosses the placenta and is accumulated in fetal organs, including the brain. High exposure to inorganic lead can induce intrauterine death and stillbirth. At lower levels, prenatal exposure to lead, indicated by cord blood lead level obtained at parturition, is associated with a range of adverse effects, including decreased growth in stature and delays in early infant development. If no further elevated lead exposure occurs after birth, development generally, but not always, normalizes, as demonstrated in longitudinal studies in which the subjects were enrolled prior to birth (Bellinger et al. 1992).

6.2.6 Cardiovascular toxicity

Several studies have reported significant associations between blood lead level and blood pressure in adult men and women (Hertz-Picciotto and Croft 1993, ATSDR 1999). In both of the NHANES surveys (II and III) of lead exposure and health status in the United States, blood lead level was positively associated with blood pressure, in a dose-related fashion. It was estimated that the effects of lead exposure on blood pressure contribute significantly to risks of hypertensive heart disease and stroke in the U.S. population.

6.2.7 Other effects in rodents

It is important to note that all of these toxic effects of lead described in human populations have been observed in rodent models at similar blood lead levels. Lead induces both PNS and CNS toxicity; affects CNS development in young animals,

resulting in impaired learning performance and hyperactivity; inhibits heme biosynthesis; affects intrauterine growth; affects auditory-evoked responses; impairs reproductive function in males; and induces hypertension.