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j.scitotenv.2010.04.027)
Science of the Total Environment 435–436 (2012) 580–581
Contents lists available at ScienceDirect
Science of the Total Environment j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c i t o t e n v
Letter to the Editor re Lettmeier et al. (2010): Proposal for a Revised Reference Concentration (RfC) for mercury vapour in adults, Sci Total Environ (2010, doi:10.1016/ j.scitotenv.2010.04.027) Keywords: Mercury vapour Reference air concentration RfC Uncertainty factors
This paper offers the opportunity for advancement in the assessment of toxicity from exposure to mercury vapour, and a basis for a revised reference air concentration (RfC) that does not rely on data collected decades ago. The data present two significant advantages for the setting of a RfC:
• The toxicological data relate to what can be considered clinical signs and symptoms rather than sub-clinical measures of neurotoxicity, the latter often the cause for debate regarding significance for human health risk assessment; • The mercury vapour exposures can be safely assumed to have been free of concomitant exposure to chlorine gas, the latter which occurs in studies of chloralkali workers and which alters the chemical form, absorption and toxic effects of mercury vapour (reviewed by Richardson et al., 2009).
Our main comments relate to the appropriate uncertainty factors (UFs) that might be applied by regulatory agencies towards establishing a RfC for mercury vapour employing this study. In our view, the authors did not give this subject sufficient critical consideration. First, it is unclear from the paper whether the authors interpret the “cut-off values” for mercury levels in urine, blood or hair as being no-observed-adverse-effect-levels (NOAELs) or lowest-observable-adverse-effect-levels (LOAELs). When discussing uncertainty factors for application to setting a RfC, the authors consider a UF for LOAEL to NOAEL extrapolation, as per the US EPA and the EU. However, in the text, reference is made to these cut-off values as “threshold limits”. We believe that these cut-off values represent LOAELs, but this discrepancy should be clarified as the interpretation of these cut-off values as either LOAELs or NOAELs will have significant implications for the determination of appropriate UFs. Second, the reported cut-off values relate to adults only. Therefore, to derive a RfC that is applicable to all age groups, a UF specific to address inter-individual variation in toxic response will be required, in particular for extrapolation from adults to children, the latter being
0048-9697/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.scitotenv.2010.08.064
broadly identified as a sensitive subpopulation for the effects of neurotoxicants such as mercury (EPA, 1998). Third, the authors made specific reference to a lack of published studies on “…gender-specific differences in regard to negative health effects of mercury vapour…” Although the database for genderspecific toxic effects may be limited, there are several studies on gender differences in the pharmacokinetics of mercury vapour, which were summarized by Richardson et al. (2009). Those studies suggest that females are at greater risk of absorbing and retaining mercury, and of having higher accumulation in the brain. Therefore, gender differences in toxicology probably exist. It is noted that the cohorts of the subject study include both men and women. This would permit the analysis of data for each gender separately to determine if one gender was more sensitive. We encourage the conduct and publication of this gender-specific analysis. Alternately or additionally, the lower 95% confidence limit for the defined cut-off values could be determined from the full dataset (genders combined), such as by following the dose– response analysis recommendations of the US NRC (2009). Then, the cut-off values would be defined such that inter-individual (for adults, at least) and inter-gender variation in toxic response would already be included in the determination of the cut-off value. Finally, it will be important for the regulatory interpretation of this study, towards updating and revising the RfC for mercury vapour, that the data, the extant toxicological database, and other relevant factors be critically re-examined de novo. The California EPA recently updated its chronic REL for mercury vapour (CalEPA, 2008) to 0.03 μg/m3, assigning a total UF of 300 (rather than 30 as per US EPA), in consideration of the same key studies considered by the US EPA (1995). However, the final determination of appropriate UFs is critically dependent on the specific key study or studies selected for chronic RfC development. We must resist the simple adoption of previous UFs that were defined for application to another study, in another era, and for a far more limited toxicological database, as was the case in 1995 when the EPA last revised its RfC for mercury vapour. References CalEPA (California Environmental Protection Agency). Mercury (7439-97-6) and inorganic mercury compounds. OEHHA Acute, 8-hour and Chronic Reference Exposure Level (REL)s. Office of Environmental Health Hazard Assessment, California EPA. Dated December 2008; 2008. Available from: http://www.oehha. ca.gov/air/allrels.html. Details regarding the derivation of the CalEPA chronic REL, and assigned UFs, are available from: bhttp://www.oehha.ca.gov/air/hot_ spots/2008/AppendixD1_final.pdf#page=214N. Richardson GM, Brecher RW, Scobie H, Hamblen J, Phillips K, Samuelian J, Smith C. Mercury vapour (Hg0): continuing toxicological uncertainties, and establishing a Canadian reference exposure level. Regulatory Toxicology and Pharmacology 2009;53:32–8. US EPA (United States Environmental Protection Agency). Guidelines for Neurotoxicity Risk Assessment. Report EPA/630/R-95/001F, Dated April 1998. Washington, DC: U.S. Environmental Protection Agency; 1998.
581 US NRC (United States National Research Council. Science and decisions: advancing risk assessment. Committee on improving risk analysis approaches used by the U.S. EPA. Washington, DC: The National Academies Press; 2009. ISBN: 0-309-12047-0.
G. Mark Richardson SNC-Lavalin Environment, Suite 110, 20 Colonnade Road, Ottawa, ON, Canada K2E 7M6 Corresponding author. Tel.: + 1 613 226 2456x228; fax: +1 613 226 9980. E-mail address: [email protected].
Ronald W. Brecher GlobalTox, a Division of MTE Consultants Inc., 255 Speedvale Ave. W., Guelph, ON, Canada, N1H 1C5 Tel.: + 1 519 766 1000x223; fax: +1 519 766 1100. E-mail address: [email protected]. 3 August 2010
Contents lists available at ScienceDirect
Science of the Total Environment j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c i t o t e n v
Letter to the Editor re Lettmeier et al. (2010): Proposal for a Revised Reference Concentration (RfC) for mercury vapour in adults, Sci Total Environ (2010, doi:10.1016/ j.scitotenv.2010.04.027) Keywords: Mercury vapour Reference air concentration RfC Uncertainty factors
This paper offers the opportunity for advancement in the assessment of toxicity from exposure to mercury vapour, and a basis for a revised reference air concentration (RfC) that does not rely on data collected decades ago. The data present two significant advantages for the setting of a RfC:
• The toxicological data relate to what can be considered clinical signs and symptoms rather than sub-clinical measures of neurotoxicity, the latter often the cause for debate regarding significance for human health risk assessment; • The mercury vapour exposures can be safely assumed to have been free of concomitant exposure to chlorine gas, the latter which occurs in studies of chloralkali workers and which alters the chemical form, absorption and toxic effects of mercury vapour (reviewed by Richardson et al., 2009).
Our main comments relate to the appropriate uncertainty factors (UFs) that might be applied by regulatory agencies towards establishing a RfC for mercury vapour employing this study. In our view, the authors did not give this subject sufficient critical consideration. First, it is unclear from the paper whether the authors interpret the “cut-off values” for mercury levels in urine, blood or hair as being no-observed-adverse-effect-levels (NOAELs) or lowest-observable-adverse-effect-levels (LOAELs). When discussing uncertainty factors for application to setting a RfC, the authors consider a UF for LOAEL to NOAEL extrapolation, as per the US EPA and the EU. However, in the text, reference is made to these cut-off values as “threshold limits”. We believe that these cut-off values represent LOAELs, but this discrepancy should be clarified as the interpretation of these cut-off values as either LOAELs or NOAELs will have significant implications for the determination of appropriate UFs. Second, the reported cut-off values relate to adults only. Therefore, to derive a RfC that is applicable to all age groups, a UF specific to address inter-individual variation in toxic response will be required, in particular for extrapolation from adults to children, the latter being
0048-9697/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.scitotenv.2010.08.064
broadly identified as a sensitive subpopulation for the effects of neurotoxicants such as mercury (EPA, 1998). Third, the authors made specific reference to a lack of published studies on “…gender-specific differences in regard to negative health effects of mercury vapour…” Although the database for genderspecific toxic effects may be limited, there are several studies on gender differences in the pharmacokinetics of mercury vapour, which were summarized by Richardson et al. (2009). Those studies suggest that females are at greater risk of absorbing and retaining mercury, and of having higher accumulation in the brain. Therefore, gender differences in toxicology probably exist. It is noted that the cohorts of the subject study include both men and women. This would permit the analysis of data for each gender separately to determine if one gender was more sensitive. We encourage the conduct and publication of this gender-specific analysis. Alternately or additionally, the lower 95% confidence limit for the defined cut-off values could be determined from the full dataset (genders combined), such as by following the dose– response analysis recommendations of the US NRC (2009). Then, the cut-off values would be defined such that inter-individual (for adults, at least) and inter-gender variation in toxic response would already be included in the determination of the cut-off value. Finally, it will be important for the regulatory interpretation of this study, towards updating and revising the RfC for mercury vapour, that the data, the extant toxicological database, and other relevant factors be critically re-examined de novo. The California EPA recently updated its chronic REL for mercury vapour (CalEPA, 2008) to 0.03 μg/m3, assigning a total UF of 300 (rather than 30 as per US EPA), in consideration of the same key studies considered by the US EPA (1995). However, the final determination of appropriate UFs is critically dependent on the specific key study or studies selected for chronic RfC development. We must resist the simple adoption of previous UFs that were defined for application to another study, in another era, and for a far more limited toxicological database, as was the case in 1995 when the EPA last revised its RfC for mercury vapour. References CalEPA (California Environmental Protection Agency). Mercury (7439-97-6) and inorganic mercury compounds. OEHHA Acute, 8-hour and Chronic Reference Exposure Level (REL)s. Office of Environmental Health Hazard Assessment, California EPA. Dated December 2008; 2008. Available from: http://www.oehha. ca.gov/air/allrels.html. Details regarding the derivation of the CalEPA chronic REL, and assigned UFs, are available from: bhttp://www.oehha.ca.gov/air/hot_ spots/2008/AppendixD1_final.pdf#page=214N. Richardson GM, Brecher RW, Scobie H, Hamblen J, Phillips K, Samuelian J, Smith C. Mercury vapour (Hg0): continuing toxicological uncertainties, and establishing a Canadian reference exposure level. Regulatory Toxicology and Pharmacology 2009;53:32–8. US EPA (United States Environmental Protection Agency). Guidelines for Neurotoxicity Risk Assessment. Report EPA/630/R-95/001F, Dated April 1998. Washington, DC: U.S. Environmental Protection Agency; 1998.
581 US NRC (United States National Research Council. Science and decisions: advancing risk assessment. Committee on improving risk analysis approaches used by the U.S. EPA. Washington, DC: The National Academies Press; 2009. ISBN: 0-309-12047-0.
G. Mark Richardson SNC-Lavalin Environment, Suite 110, 20 Colonnade Road, Ottawa, ON, Canada K2E 7M6 Corresponding author. Tel.: + 1 613 226 2456x228; fax: +1 613 226 9980. E-mail address: [email protected].
Ronald W. Brecher GlobalTox, a Division of MTE Consultants Inc., 255 Speedvale Ave. W., Guelph, ON, Canada, N1H 1C5 Tel.: + 1 519 766 1000x223; fax: +1 519 766 1100. E-mail address: [email protected]. 3 August 2010