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1 Genotoxictiy available data for inorganic lead salts

In view of the ubiquitous nature of environmental lead contamination, genotoxicity studies are important from two standpoints: assessing the potential for genetic damage in humans and furthering our knowledge of the mechanism of renal carcinogenesis in rodents. Genotoxicity studies in non-mammalian and mammalian animal systems and in humans have been extensively reviewed.1-7 A critical review on lead toxicology is compiled by Cohen and Roe8 from which parts of the assessment of genotoxicity are summarized below.

1.1 Data from experimental assays

About 40 tests have been conducted on inorganic lead salts, mainly with negative results.9 Tests for DNA damage or gene mutation in bacteria, gene mutation or mitotic recombination in yeast, and aneuploidy in Drosophila all proved negative9, 10. Tests in vivo for unscheduled DNA synthesis in rodents were also negative.9 Conflicting results have been obtained in tests for sister chromatid exchanges (SCEs). Negative results were reported in vitro11 and in vivo9, but a positive result was reported in vivo by Sharma et al..12 In the latter study a small but statistically significant increase in SCEs was observed in mice given an ip dose of 200 mg/kg body weight, but this weak response needs to be weighed against the negative response at the lower dose of 50 mg/body weight and against the variability of spontaneous control frequencies of SCEs. When these facts are taken into account, Cohen and Roe8 conclude that the finding in reference 12 is not convincing. Cell transformation assays also gave conflicting results; positive results being reported in cultured BALB/c3T3, or SA7/SHE cells but negative results with SHE, clonal assay and RLV/Fischer rats.9 More recent cell transformation tests13 with lead acetate at the limit of solubility (10µg/ml) and in the insolubility range (20 µg/ml) gave negative results. The mouse sperm head abnormalities assay gave positive findings4, 10 but a non-genetic cellular effect may account for these findings, especially at the high doses of lead acetate used, and this assay system cannot be regarded as providing unequivocal evidence of genotoxicity. Of four micronucleus tests conducted in vivo, three gave negative results and one a questionable positive result.4 Of five tests conducted in vivo for chromosomal aberrations, two were negative and three questionably positive.4 Lead acetate can inhibit DNA and RNA synthesis readily in isolated nuclei but with difficulty in intact cells,14 thus, inhibition is dependent on cell membrane permeability. It is conceivable that at very high exposure levels in vivo or under in vitro conditions, where membrane barriers may be only partially effective, the resultant cellular entry would result in chromosomal damage. As this could be regarded as an indirect effect, the existence both of a threshold dose level and of a complete reversibility of effect are real possibilities. The in vivo studies suggest that acute exposures to high concentrations of lead salts may result in small but statistically significant elevations of chromosomal aberrations but chronic exposures to lower, but still high, levels of lead salts appear to have no effect on mammalian chromosomes (Brusick, 1987 unpublished report). Schaaper et al. investigated various metals and metal salts for their ability to produce apurinic sites in DNA (a mechanism that could explain why some metals are mutagenic) and in a separate study they treated qSX174 phage DNA with metals followed by transfecting the DNA into Escherichia coli sphereo-blasts, survival of the DNA being directly dependent upon the number of apurinic sites.15 It was found that lead acetate did not produce the number or type of reactions common to genotoxic metals or metal salts.

1.2 Human data

Studies, mainly in workers occupationally exposed to lead for chromosomal abnormalities, have been reviewed.1-7 No evidence was obtained in vitro of DNA damage or chromosomal aberrations in lymphocytes.9 Conflicting results have been obtained in tests for SCE and chromosomal aberrations in vivo but IARC classification did not assign a positive response for the overall results of either of these endpoints.9 Increased incidences of SCEs have been reported in the lymphocytes of workers exposed to lead but not in children exposed to high levels of lead in the environment.9 Of 18 studies, 11 have reportedly shown chromosomal changes (blood lead 10-100 µg/100 ml) whilst seven have shown no association (blood lead 4-50/µg/100 ml).1, 2, 5, 9, 16

However, in the case of most of these studies there has been exposure to a cocktail of other metals and chemicals, particularly in the case of smelter workers. The evidence incriminating occupational exposure to lead per se, even at high levels, is far from convincing. It is most unlikely that exposure to much lower levels of environmental lead presents any genotoxic risk to man.

1.3 Conclusion

In its review of lead genotoxicity, the classification scheme adopted by IARC9 did not assign a positive endpoint to any of the sub mammalian and mammalian systems in vitro or in vivo. The overall results indicate that lead salts are not directly genotoxic and, at low exposure levels, pose no risk for somatic or germ cell mutation. At high exposure levels there is evidence of a slight elevation of chromosomal aberrations but whether or not this represents an indirect effect of lead exposure remains to be established. The EPA17 and ATSDR1 have also drawn attention to the conflicting results in mammalian systems in vitro and in vivo but consider that the weight of evidence suggests a clastogenic effect, possibly associated with the status of calcium nutrition.

Based on all available information no positive endpoint to any of the sub mammalian and mammalian systems in vitro or in vivo could be assigned.

2 References

1.ATSDR Toxicological profile for lead; 1999.

2.EPA Air quality criteria for lead; US Environmental Protection Agency, Research Triangle Park, NC 27711: 1986.

3.IARC IARC Monographs of carcinogenic risks to humans, Suppl. 7; International Agency for Research on Cancer: Lyons, 1987; pp 230-231.

4.IARC Lead and lead compounds. In: Overall evaluations of carcinogenicity: an updating of IARC Monographs, Volumes 1 to 42.; International Agency for Research on Cancer: Lyon, 1987; pp 230-232.

5.IARC Some metals and metallic compounds. In: Overall evaluations of carcinogenicity: an updating of IARC Monographs, Volume 23.; International Agency for Research on Cancer: Lyon, 1980; pp 325-415.

6.WHO Safety Evaluation of Certain Food Additives and Contaminants WHO: Geneva, 2000.

7.US Nutrition Foundation A report of the Nutrition Foundation's Expert Advisory Committee. Assessment of the safety of lead and lead salts in food.; 1982; pp 1-110.

8.Cohen, A. J.; Roe, F. J., Review of lead toxicology relevant to the safety assessment of lead acetate as a hair colouring. Food & Chemical Toxicology 1991, 29, (7), 485-507.

9.IARC Genetic and related effects: An updating of selected IARC Monographs from Volumes 1 to 42.; International Agency for Research on Cancer: Lyon, 1987.

10.Hollstein, M.; McCann, J.; Angelosanto, F. A.; Nichols, W. W., Short-term tests for carcinogens and mutagens. Mutation Research 1979, 65, (3), 133-226.

11.Abe, S.; Sasaki, M., SCE as an index of mutagenesis and/or carcinogenesis. In Sister Chromatide Exchange, Wolff, S., Ed. Alan R. Liss: New York, 1982; pp 461-514.

12.Sharma, R. K.; Jacobson-Kram, D.; Lemmon, M.; Bakke, J.; Galperin, I.; Blazak, W. F., Sister-chromatid exchange and cell replication kinetics in fetal and maternal cells after treatment with chemical teratogens. Mutation Research 1985, 158, (3), 217-31.

13.Dunkel, V. C.; Schechtman, L. M.; Tu, A. S.; Sivak, A.; Lubet, R. A.; Cameron, T. P., Interlaboratory evaluation of the C3H/10T1/2 cell transformation assay. Environmental & Molecular Mutagenesis 1988, 12, (1), 21-31.

14.Frenkel, G. D.; Middleton, C., Effects of lead acetate on DNA and RNA synthesis by intact HeLa cells, isolated nuclei and purified polymerases. Biochemical Pharmacology 1987, 36, (2), 265-8.

15.Schaaper, R. M.; Koplitz, R. M.; Tkeshelashvili, L. K.; Loeb, L. A., Metal-induced lethality and mutagenesis: possible role of apurinic intermediates. Mutation Research 1987, 177, (2), 179-88.

16.Forni, A.; Sciame, A.; Bertazzi, P. A.; Alessio, L., Chromosome and biochemical studies in women occupationally exposed to lead. Archives of Environmental Health 1980, 35, (3), 139-46.

17.US EPA Air quality criteria for lead.; Environmental Protection Agency: Washongton, DC, 1986.


Short description of key information:
The overall results indicate that lead salts are not directly genotoxic and, at low exposure levels, pose no risk for somatic or germ cell mutation. At high exposure levels there is evidence of a slight elevation of chromosomal aberrations but whether or not this represents an indirect effect of lead exposure remains to be established. The EPA and ATSDR have also drawn attention to the conflicting results in mammalian systems in vitro and in vivo but consider that the weight of evidence suggests a clastogenic effect, possibly associated with the status of calcium nutrition.
Based on all available information no positive endpoint to any of the sub mammalian and mammalian systems in vitro or in vivo could be assigned.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The available data published for lead salts do not indicate a positive endpoint to any of the sub mammalian and mammalian systems in vitro or in vivo, thus lead acetate basic and lead acetate dibasic do not need to be classified according to 67/548/EC or CLP.