Archived Comments for:
Oral ingestion of hexavalent chromium through drinking water and cancer mortality in an industrial area of Greece - An ecological study
We find the ecological study of Linos et al. of interest but disagree that the finding ¿supports the hypothesis of hexavalent chromium (Cr+6) carcinogenicity via the oral ingestion pathway of exposure.¿ Potential confounding by personal or occupational exposures coupled with poorly defined Cr+6 ingestion exposures raise serious concerns about the validity of the hypothesized association. In ecological studies such as this, where the population group is the unit of observation for exposure and outcome, it is also important to consider ecological bias--the failure of the reported association to reflect an association at the individual level.
Whether Cr+6 poses a cancer risk from ingestion exposures in humans is an important public health question (Stout et al. 2008). Occupational epidemiological studies have associated inhalation exposures with increased lung cancer. However, an increased risk of other cancers has not been consistently reported from occupational exposures (Gatto et al. 2010). There is scant epidemiological information about cancer risks associated with the ingestion of environmental levels of Cr+6. Since the study of Linos et al. does not provide information about a possible casual association, we urge caution in the use of these data as the basis for making regulatory decisions about waterborne levels of Cr+6.
Municipalities in the study area were transformed into industrial areas beginning in the early 1970s with little or no restrictions on disposal of liquid industrial wastes into the Asopos River, which runs through Oinofita, the municipality with elevated cancer mortality. In 2009 there were 700 industries operating in the area with 500 generating undisclosed liquid industrial waste. Occupational, airborne, waterborne, or other environmental exposures to a wide range of undisclosed chemicals could account for the reported elevated risks. If liquid wastes were discharged into the surface and/or ground water sources during the period of industrialization, various chemicals would undoubtedly be present in Oinofita municipal water, possibly contributing to confounding or effect modification. Modest concentrations of arsenic were found in the water, and it is possible that other chemicals may have been present but not measured. Linos et al. note that the available water quality measurements for Oinofita water did not reveal high concentrations of other substances but do not provide a list of chemicals that were measured.
The authors also note that the highest concentration (156 ppb) of Cr+6 was measured in a well close to the village of Agios Thomas (population 1090) and that three of the six liver cancer deaths were among residents of this village. Agios Thomas is one of the four villages in Oinofita municipality. This information seems to have been presented as evidence of a strong association between waterborne Cr+6 and liver cancer mortality, but readers are not informed whether the contaminated well is part of the Oinofita municipal system and used by residents of Agios Thomas. Rather, the authors offer contradictory statements about this specific exposure: ¿...exposure is expressed as residing in the area assuming that all residents consumed water provided by the municipality (Oinofita)¿ and ¿Well water is very rarely used for drinking in Greece and the level of contamination is very similar.¿ Confusion about the use of this contaminated well also raises concerns that the assumed ecological exposures may not necessarily reflect individual exposures.
Exposure misclassification bias is also possible as ¿Initial concerns were raised after Oinofita area citizens complained about the discoloration and turbidity of their drinking water....¿ with regular protests from 1990s onward. Beaumont et al. (2008) noted that waterborne exposure to Cr+6 in an ecological study in China may have been self-limiting due to the lack of palatability of drinking water at high concentrations of Cr+6. Armienta-Hernandez and Rodriguez-Castillo (1995) also noted that participants in a study in Mexico did not consume water because of the yellowish color associated with Cr+6 concentrations above 500 ppb. Oinofita residents may also have limited their consumption of municipal water and used alternative sources of drinking water (e.g., bottled water). Bottled water use would lower actual exposures, and if bottled water use had been more prevalent among Oinofita residents, nondifferential misclassification bias would result in an over estimate of risk in the current analysis.
All death certificates were scrutinized to exclude all metastatic liver cancers, and this reduces the likelihood for the misclassification of liver cancer mortality. While this strengthens the finding of elevated risks of liver cancer in Oinofita, it does not address the possibility that hepatitis B infection or alcohol consumption may be contributing risk factors. We agree with and strongly support the authors¿ recommendation that ¿Further studies are needed to determine whether this association is causal, and to establish preventative guidelines and public health recommendations.¿ However, to better understand possible risks associated with the ingestion of environmental levels of Cr+6, additional epidemiological studies should not use an ecological study design.
Competing interests
We have no competing interests. We accepted an honorarium from the American Chemistry Council to review this article. These comments are based on our review.
Response
Athena Linos, University of Athens
5 June 2012
Gunther Craun questions the validity of our study ¿Oral ingestion of hexavalent chromium through drinking water and cancer mortality in an industrial area of Greece - An ecological study¿ and subsequently questions the causality of the observed association between oral exposure to hexavalent chromium and cancer. He also suggests that our study should not be used for regulatory purposes. We respond to his concerns on the study below, but also consider the relevance of the precautionary principle in making a regulatory decision on matters such as this. Indeed, we believe that given the strong biological plausibility of this association and because the outcome, cancer, is of serious public health concern, our study offers important information and sufficient evidence to call for immediate application of the precautionary principle.
Gunther Craun bases his argument for delaying making preventative guidelines and public health recommendations on the ¿ecological¿ design of the study and the potential ecological bias due to the role of potential confounders and effect modifiers. Indeed we opted to characterize our report as a report on an ¿ecological¿ study although the design is actually a combination of i) a partially ecologic study- given that the outcome (death from cancer by cancer type) is at individual level and ii) a historical cohort design with regards to exposure. He discusses alcohol consumption, smoking, hepatitis and exposure to air and water pollutants as potential confounders. As we have stated in the study, we have already controlled for some potential confounders such as age, gender, and calendar year in residence.
As far as the role of potential confounders such as alcohol consumption, smoking and hepatitis exposure we have no indication of different rates in the comparison population in our analysis. To secure that these factors did not play a confounding role, we performed independent comparisons not only with the general population of Greece but also with the Prefecture of Viotia. We found no differences in the results. With regards to the exposure to other pollutants, we present water pollutants measured during the period of follow up along with chromium and arsenic by the municipality in the attached table. No values higher than the allowed levels were observed in any measurement. The very nature of our variable of interest led to the use of group data with regards to exposure but exposure was expressed uniformly as ¿one group exposure¿- the same in the entire municipality. Ecological bias can more often occur in cases where more than one community with different levels of exposure to confounders is included in the analysis. Since we only dealt with exposure as one municipality, this is not a large risk in our study.
Needless to say that in most studies, exposure misclassification leads to underestimation of the effect (a bias towards a null result) and this would be the case, if a proportion of the population used bottled water and therefore was not exposed but classified as exposed.
As far as causality is concerned, biological plausibility and some type of dose response relationship is usually sufficient to provide strong evidence for a causal mechanism in an observational study. Several animal studies have shown that hexavalent chromium is both genotoxic and cytotoxic and has produced several types of cancer in the gastrointestinal track. Hexavalent chromium definitely metabolizes differently than the non toxic trivalent chromium and remains present in the blood after high level oral exposure. Therefore it is not completely metabolized in the acidic environment of the stomach. Furthermore hexavalent chromium is a known carcinogen to humans when exposed through inhalation. Based on the previous arguments, we strongly believe that the association between oral exposure to hexavalent chromium and cancer is biologically plausible.
As far as a dose relationship is concerned, our study could not lead to estimates of exposure dose. We consider, though, that the observed increase of the SMRs in the last year of observation is an indication of a dose response relationship.
As mentioned, Gunther Craun also argues that since there may be questions regarding elements of the study, that regulatory reform should not be based on these findings. Although it is up to the discretion of each regulatory agency to decide whether or not to use the results of an observational study, it is important to note that in most countries, and definitely in the EU and the USA, the precautionary principle prevails.
The World Health Organization (WHO) and governments have repeatedly affirmed that scientific uncertainty should not prevent protection measures. For example, Article 191 of the Treaty on the Functioning of the European Union, and a number of WHO publications including ¿The precautionary principle: protecting public health, the environment and the future of our children¿ (WHO 2004), have underscored this. Principle 15 of the Rio Declaration of the 1992 United Nations Conference on Environment and Development (UNCED) reads: ¿In order to protect the environment, the precautionary approach shall be widely used by States according to their capabilities. When there are threats of serious and irreversible damage, lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation.¿ Several courts in the USA have also stated that it is better for regulators to err on the side of caution especially when the effect is serious and irreversible. Undoubtedly cancer is both a serious and, in many instances, an irreversible event and therefore despite limitations in our study, the conclusion should not be to ignore these findings, but rather to encourage further analytical epidemiological studies while taking a precautionary approach in the interim.
Ultimately, we agree that further analytical epidemiologic studies on this issue are needed and that it is important to supplement the ecologic with individual-level information. Working in this direction, we continue investigations in the area that would give us the opportunity to have (among other data) estimates on individual exposures. However, until ours and other studies are complete, we strongly believe our published data provide enough evidence to call for immediate application of the precautionary principle.
Table: Pollutants measured by the municipal authority for which values higher than the permissible levels were never detected (period: June 2005-July 2010)
Pollutant No. of measurements
Al (Aluminium) 34
B (Boron) 11
Cd (Cadmium) 30
Cr (Total Chromium) 77
Cu (Copper) 18
Fe (Iron) 73
Hg (Mercury) 9
Mn (Manganese) 22
Ni (Nickel) 71
Pb (Lead) 32
Sb (Antimony) 11
Se (Selenium) 11
Environmental Health
Ecological bias?
5 June 2012
We find the ecological study of Linos et al. of interest but disagree that the finding ¿supports the hypothesis of hexavalent chromium (Cr+6) carcinogenicity via the oral ingestion pathway of exposure.¿ Potential confounding by personal or occupational exposures coupled with poorly defined Cr+6 ingestion exposures raise serious concerns about the validity of the hypothesized association. In ecological studies such as this, where the population group is the unit of observation for exposure and outcome, it is also important to consider ecological bias--the failure of the reported association to reflect an association at the individual level.
Whether Cr+6 poses a cancer risk from ingestion exposures in humans is an important public health question (Stout et al. 2008). Occupational epidemiological studies have associated inhalation exposures with increased lung cancer. However, an increased risk of other cancers has not been consistently reported from occupational exposures (Gatto et al. 2010). There is scant epidemiological information about cancer risks associated with the ingestion of environmental levels of Cr+6. Since the study of Linos et al. does not provide information about a possible casual association, we urge caution in the use of these data as the basis for making regulatory decisions about waterborne levels of Cr+6.
Municipalities in the study area were transformed into industrial areas beginning in the early 1970s with little or no restrictions on disposal of liquid industrial wastes into the Asopos River, which runs through Oinofita, the municipality with elevated cancer mortality. In 2009 there were 700 industries operating in the area with 500 generating undisclosed liquid industrial waste. Occupational, airborne, waterborne, or other environmental exposures to a wide range of undisclosed chemicals could account for the reported elevated risks. If liquid wastes were discharged into the surface and/or ground water sources during the period of industrialization, various chemicals would undoubtedly be present in Oinofita municipal water, possibly contributing to confounding or effect modification. Modest concentrations of arsenic were found in the water, and it is possible that other chemicals may have been present but not measured. Linos et al. note that the available water quality measurements for Oinofita water did not reveal high concentrations of other substances but do not provide a list of chemicals that were measured.
The authors also note that the highest concentration (156 ppb) of Cr+6 was measured in a well close to the village of Agios Thomas (population 1090) and that three of the six liver cancer deaths were among residents of this village. Agios Thomas is one of the four villages in Oinofita municipality. This information seems to have been presented as evidence of a strong association between waterborne Cr+6 and liver cancer mortality, but readers are not informed whether the contaminated well is part of the Oinofita municipal system and used by residents of Agios Thomas. Rather, the authors offer contradictory statements about this specific exposure: ¿...exposure is expressed as residing in the area assuming that all residents consumed water provided by the municipality (Oinofita)¿ and ¿Well water is very rarely used for drinking in Greece and the level of contamination is very similar.¿ Confusion about the use of this contaminated well also raises concerns that the assumed ecological exposures may not necessarily reflect individual exposures.
Exposure misclassification bias is also possible as ¿Initial concerns were raised after Oinofita area citizens complained about the discoloration and turbidity of their drinking water....¿ with regular protests from 1990s onward. Beaumont et al. (2008) noted that waterborne exposure to Cr+6 in an ecological study in China may have been self-limiting due to the lack of palatability of drinking water at high concentrations of Cr+6. Armienta-Hernandez and Rodriguez-Castillo (1995) also noted that participants in a study in Mexico did not consume water because of the yellowish color associated with Cr+6 concentrations above 500 ppb. Oinofita residents may also have limited their consumption of municipal water and used alternative sources of drinking water (e.g., bottled water). Bottled water use would lower actual exposures, and if bottled water use had been more prevalent among Oinofita residents, nondifferential misclassification bias would result in an over estimate of risk in the current analysis.
All death certificates were scrutinized to exclude all metastatic liver cancers, and this reduces the likelihood for the misclassification of liver cancer mortality. While this strengthens the finding of elevated risks of liver cancer in Oinofita, it does not address the possibility that hepatitis B infection or alcohol consumption may be contributing risk factors. We agree with and strongly support the authors¿ recommendation that ¿Further studies are needed to determine whether this association is causal, and to establish preventative guidelines and public health recommendations.¿ However, to better understand possible risks associated with the ingestion of environmental levels of Cr+6, additional epidemiological studies should not use an ecological study design.
Competing interests
We have no competing interests. We accepted an honorarium from the American Chemistry Council to review this article. These comments are based on our review.
Response
5 June 2012
Gunther Craun questions the validity of our study ¿Oral ingestion of hexavalent chromium through drinking water and cancer mortality in an industrial area of Greece - An ecological study¿ and subsequently questions the causality of the observed association between oral exposure to hexavalent chromium and cancer. He also suggests that our study should not be used for regulatory purposes. We respond to his concerns on the study below, but also consider the relevance of the precautionary principle in making a regulatory decision on matters such as this. Indeed, we believe that given the strong biological plausibility of this association and because the outcome, cancer, is of serious public health concern, our study offers important information and sufficient evidence to call for immediate application of the precautionary principle.
Gunther Craun bases his argument for delaying making preventative guidelines and public health recommendations on the ¿ecological¿ design of the study and the potential ecological bias due to the role of potential confounders and effect modifiers. Indeed we opted to characterize our report as a report on an ¿ecological¿ study although the design is actually a combination of i) a partially ecologic study- given that the outcome (death from cancer by cancer type) is at individual level and ii) a historical cohort design with regards to exposure. He discusses alcohol consumption, smoking, hepatitis and exposure to air and water pollutants as potential confounders. As we have stated in the study, we have already controlled for some potential confounders such as age, gender, and calendar year in residence.
As far as the role of potential confounders such as alcohol consumption, smoking and hepatitis exposure we have no indication of different rates in the comparison population in our analysis. To secure that these factors did not play a confounding role, we performed independent comparisons not only with the general population of Greece but also with the Prefecture of Viotia. We found no differences in the results. With regards to the exposure to other pollutants, we present water pollutants measured during the period of follow up along with chromium and arsenic by the municipality in the attached table. No values higher than the allowed levels were observed in any measurement. The very nature of our variable of interest led to the use of group data with regards to exposure but exposure was expressed uniformly as ¿one group exposure¿- the same in the entire municipality. Ecological bias can more often occur in cases where more than one community with different levels of exposure to confounders is included in the analysis. Since we only dealt with exposure as one municipality, this is not a large risk in our study.
Needless to say that in most studies, exposure misclassification leads to underestimation of the effect (a bias towards a null result) and this would be the case, if a proportion of the population used bottled water and therefore was not exposed but classified as exposed.
As far as causality is concerned, biological plausibility and some type of dose response relationship is usually sufficient to provide strong evidence for a causal mechanism in an observational study. Several animal studies have shown that hexavalent chromium is both genotoxic and cytotoxic and has produced several types of cancer in the gastrointestinal track. Hexavalent chromium definitely metabolizes differently than the non toxic trivalent chromium and remains present in the blood after high level oral exposure. Therefore it is not completely metabolized in the acidic environment of the stomach. Furthermore hexavalent chromium is a known carcinogen to humans when exposed through inhalation. Based on the previous arguments, we strongly believe that the association between oral exposure to hexavalent chromium and cancer is biologically plausible.
As far as a dose relationship is concerned, our study could not lead to estimates of exposure dose. We consider, though, that the observed increase of the SMRs in the last year of observation is an indication of a dose response relationship.
As mentioned, Gunther Craun also argues that since there may be questions regarding elements of the study, that regulatory reform should not be based on these findings. Although it is up to the discretion of each regulatory agency to decide whether or not to use the results of an observational study, it is important to note that in most countries, and definitely in the EU and the USA, the precautionary principle prevails.
The World Health Organization (WHO) and governments have repeatedly affirmed that scientific uncertainty should not prevent protection measures. For example, Article 191 of the Treaty on the Functioning of the European Union, and a number of WHO publications including ¿The precautionary principle: protecting public health, the environment and the future of our children¿ (WHO 2004), have underscored this. Principle 15 of the Rio Declaration of the 1992 United Nations Conference on Environment and Development (UNCED) reads: ¿In order to protect the environment, the precautionary approach shall be widely used by States according to their capabilities. When there are threats of serious and irreversible damage, lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation.¿ Several courts in the USA have also stated that it is better for regulators to err on the side of caution especially when the effect is serious and irreversible. Undoubtedly cancer is both a serious and, in many instances, an irreversible event and therefore despite limitations in our study, the conclusion should not be to ignore these findings, but rather to encourage further analytical epidemiological studies while taking a precautionary approach in the interim.
Ultimately, we agree that further analytical epidemiologic studies on this issue are needed and that it is important to supplement the ecologic with individual-level information. Working in this direction, we continue investigations in the area that would give us the opportunity to have (among other data) estimates on individual exposures. However, until ours and other studies are complete, we strongly believe our published data provide enough evidence to call for immediate application of the precautionary principle.
Table: Pollutants measured by the municipal authority for which values higher than the permissible levels were never detected (period: June 2005-July 2010)
Pollutant No. of measurements
Al (Aluminium) 34
B (Boron) 11
Cd (Cadmium) 30
Cr (Total Chromium) 77
Cu (Copper) 18
Fe (Iron) 73
Hg (Mercury) 9
Mn (Manganese) 22
Ni (Nickel) 71
Pb (Lead) 32
Sb (Antimony) 11
Se (Selenium) 11
Competing interests
There are no competing interests to report.