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Key value for chemical safety assessment

Effects on fertility

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For LEAD: Animal studies serve primarily to validate mechanistic inferences drawn from studies in humans - a number of which are described in section 7.10.2. The following conclusions have been drawn from observational studies in humans.

1.     The available data indicate that extremely high lead exposure can have a marked adverse impact upon semen quality. Aberrant sperm morphology, decreased sperm count and decreased sperm density have all been demonstrated in heavily exposed individuals. However, it is difficult to precisely define the levels of exposure at which these effects will be exerted. The recently completed Asclepios Project (Bonde et al., 1999, 2002) was of sufficient size to model dose-effect relationships and indicted a threshold for an effect of concurrent blood lead upon semen quality of 45 µg/dL. Significant changes in semen quality that may adversely impact reproductive function of the individual require exposures in excess of 50 µg/dL. In the range of 50 – 60 µg/dL lead in blood, alterations in semen quality are relatively mild, but could be significant for individuals who (for other reasons) are already of marginal fertility. Lead exposure might thus be hypothesised to increase the difficulty such individuals experience in achieving conception, but such as effect has not yet been documented in association with lead exposure. Decrements in semen quality that would unambiguously impact upon fertility have been only inconsistently reported and are associated with exposure levels (e.g. require occupational exposures that produce blood lead levels of 70 µg/dL or higher) associated with clinical lead intoxication.

2.     A NOAEL of 45 µg/dL is indicated for effects upon male semen quality and thus for effects upon male fertility. At exposure levels moderately in excess of the NOAEL effects upon actual fertility will be modest.

3.     Effects upon female human fertility have been documented in the historical literature but their dosimetry is uncertain. Given that other reproductive impacts will manifest at lower doses (e.g. developmental effects), the exposure levels that may impair female fertility will be secondary to other reproductive endpoints in quantitative risk assessment. Data in females are not adequate to estimate a NOAEL for fertility, but any effects will likely manifest as secondary impacts of systemic toxicity associated with clinicallead intoxication at blood lead levels in excess of 70 µg/dL .

Short description of key information:
For LEAD: Although a number of studies have been conducted of male reproductive function in workers occupationally exposed to lead, definitive statements regarding the impact of lead upon male reproductive potential are difficult to make. Alterations in semen quality are the most commonly observed effects in the occupational setting and can be documented with precision, but such changes are not synonymous with impacts upon fertility. Natural and extreme variability in semen quality (e.g. sperm count and motility) is evident among fertile individuals and modest impacts upon semen quality(e.g. in blood lead ranges of 50 – 60 µg/dL) would not be expected to have a significant impact upon actual fertility. Higher blood lead levels would have greater impacts upon semen quality – the decrements associated with high blood lead levels would be expected to have an impact upon the fertility of normal, healthy individuals. The dosimetry for impacts upon female fertility is uncertain but appears to entail general systemic toxicity induced at blood lead levels in excess of 70 µg/dL.

Effects on developmental toxicity

Description of key information
For LEAD: The existing data indicate that lead exposure will not lead to increased frequency of congenital abnormalities in humans. Data relating prenatal blood levels to preterm delivery, gestational age and/or birth weight are mixed and provide uncertain results. Weight of evidence evaluation indicates that effects do not occur at blood lead levels up to 30 µg/dL, but are not adequate to determine the extent of the higher exposure levels that would be required to produce effects. A NOAEL of 30 µg/dL is recommended for pregnancy outcome on a precautionary basis.
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For LEAD: Effects of prenatal lead exposure upon neurobehavioural performance measures have been demonstrated in studies of experimental animals and presumably will occur in humans. However, available data are inadequate to establish the dose-effect relationships that characterize this endpoint. While effects have been observed upon early measures of mental and physical development, attenuation of effects typically occurs over time and, in most studies, are not associated with impacts upon measures such as IQ. However, effects of prenatal lead exposure upon IQ can be difficult to dissociate from those of postnatal exposure. An effect of pre-natal lead exposure has been suggested by two of nine longitudinal studies and has only been reported to persist in one. Effects observed are secondary in magnitude to those produced by exposures after birth, but blood lead levels above 10 µg/dL have been suggested to exert an effect. Although the effects under consideration would not constitute material impairment of an individual child born to a woman with a blood lead level in the range of 10 – 20 µg/dL, maintenance of the blood lead levels of pregnant women at or below 10µg/dL is advised. In essence this is designating 10 µg/dL as the NOAEL for prenatal effects of lead exposure upon neurobehavioural development in children.

Justification for classification or non-classification

Lead compounds not otherwise specified in Annex 1 of Directive 67/548/EEC are classified as follows:

                 Repr. Cat. 1; R61 (may cause harm to the unborn child)

                     Repr. Cat. 3; R62 (possible risk of impaired fertility)

Under the CLP this classification is designated as:

Repro. 1A  : (H360FD)

Classification for reproductive toxicity is supported by the experimental data and observational human studies. Evidence of impact upon human male fertility indicates consideration of Repr. Cat. 3 being changed to Repr. Cat. 1

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