VOCs and Cancer

A number of the VOCs present in indoor air have caused cancer (are “carcinogens”) in animal studies when the animals were exposed to high concentrations. A few of these VOCs – for example, formaldehyde and benzene – are considered by many authorities to be proven or probable human carcinogens [1-3]. The cancer risks from exposures to these VOCs have been estimated using exposure and risk assessment models. Some of these estimates rely on extrapolations from animals to people and all estimates rely on extrapolation from high (e.g., industrial occupational) to low pollutant doses. These models generally estimate risks for individual chemicals, and thus cannot provide information on whether exposures to simultaneous chemicals cause effects that are greater than (or less than) the sum of their individual effects. The estimation process is generally believed to use conservative assumptions that tend to overestimate cancer risks. In the field of cancer risk assessment, the general precautionary assumption has been that cancer risks increase or decrease in direct proportion to the magnitude of pollutant exposure with no threshold concentration (a concentration below which there is no increased cancer risk). If this assumption is correct, any level of indoor exposures to known carcinogens is presumed to pose some risk of cancer.

1.         Wallace, L.A., Chapter 33. Assessing human exposure to volatile organic compounds., in Indoor Air Quality Handbook, J.D. Spengler, J.M. Samet, and J.F. McCarthy, Editors. 2000, McGraw Hill: New York. p. 33.1-33.35.

2.         World Health Organization International Agency for Research on Cancer, IARC monographs on the evaluation of carcinogenic risks to humans. Volume 88 formaldehyde, 2-butoxyethanol, 1-tert-butoxypropan-2-ol. Summary of data reported and evaluation. 2006, World Health Organization Available from: http://monographs.iarc.fr/ENG/Monographs/vol88/volume88.pdf.

3.         U.S. Environmental Protection Agency. Integrated risk information system. 2005  [cited 2013 August 6]; Available from: http://www.epa.gov/iris/.

 

Studies of multiple VOCs, including formaldehyde

Loh et al. [1] estimated the cancer risks of a broad range of organic hazardous pollutants in the U.S. non-smoking population that is not occupationally exposed to these pollutants. Many of these hazardous pollutants are VOCs. For some of these VOCs such as formaldehyde, the sources are predominantly indoors. For other VOCs, the sources are predominantly outdoors, although the majority of human exposures may still occur indoors due to the entry of polluted outdoor air into buildings, where people spend most of their time. The total estimated cancer risk for the U.S. non-smoking population, from lifetime exposures to  all the hazardous pollutants considered by Loh et al., was approximately 1 in 1,000, based on cancer potency estimates from the U.S. EPA [2]. The total estimated cancer risk was 0.6 in 1,000, based on the cancer potency estimates of the California EPA [3]. Of the total estimated risk, 69% was from exposures indoors to pollutants emitted either indoors or outdoors (52% in the home), with 35% from pollutants emitted indoors. The VOCs predominantly from indoor sources that posed the largest risks were formaldehyde (approximately one in 10,000 risk), and naphthalene and chloroform (both with a risk of approximately one in 100,000). The estimated risk from paradichlorobenzene (1,4-dichlorobenzene), almost entirely from indoor sources [4], was also approximately one in 100,000. A similar risk assessment was performed for inner-city teenagers in New York City and Los Angeles [5]. For the 13 VOCs selected, the mean total estimated risk from all sources of exposure (indoors and outdoors) was approximately 1 in 1,000 in both cities. The largest sources of risk were paradichlorobenzene, formaldehyde, chloroform, acetaldehyde, and benzene. For all of these VOCs except benzene, the primary sources of exposure were indoors. More than 40% of the total risk was attributed to sources in homes.

Additional exposure and risk assessment estimates have been reported more recently.  

• Sarigiannis et al. [6] reviewed reported indoor concentrations in European countries of VOCs considered to be primary indoor pollutants: (benzene, toluene, xylenes, styrene, acetaldehyde, formaldehyde, naphthalene, limonene, alpha-pinene and ammonia). They found estimated cancer risks up to three orders of magnitude higher than the one in one million level considered an acceptable level by some risk management bodies. 
• Batterman et al. [7] reported from a study of Michigan homes that although the median indoor concentration of naphthalene was 0.89 micrograms per cubic meter (μg/m³), “14% of homes exceeded 3 μg/m³, the chronic reference concentration for non-cancer effects, 8% exceeded 10 μg/m³, and levels reached 200 μg/m³. The typical excess individual lifetime cancer risk was about one in 10,000 and reached one in 100 in some homes. Excessive use as a (moth) repellent caused the highest concentrations.” 
• Chin et al. [8] reported that indoor concentrations of p-dichlorobenzene in some Michigan homes were high: based on the California unit risk cancer estimates, 30% exceeded a cancer risk level of 1/100,000, and 4% exceeded a 1/1,000 risk level. P-dichlorobenzene has moth and pest repellents and toilet bowl and room deodorizers as indoor sources, but is used interchangeably with naphthalene in some of these products [8]. 
• Sofuoglu et al. [9] investigated indoor air levels of VOCs in Turkish primary schools. Formaldehyde had the highest carcinogenic risk levels, followed by naphthalene, benzene, and toluene due to other chronic effects. 
• Zhou et al. [10] measured personal, home indoor, work indoor, vehicle indoor, and outdoor levels of VOCs, and estimated cancer risks. “According to the cancer risk analysis of personal exposure, benzene, chloroform, carbon tetrachloride and 1,3-butadiene had median upper-bound cancer risks from lifetime exposures that exceeded the U.S. EPA benchmark of 1 cancer per one million people, and benzene presented the highest median risks at about 22 per one million. The median cumulative cancer risk of personal exposure to 5 VOCs was approximately 44 per million, followed by indoor exposure (37 per million) and in vehicle exposure (36 per million).” The next highest estimated median risks from personal exposures to individual VOCs were for 1,3 butadiene and chloroform, at about 9 and 6 per million, respectively [10].
• Hun et al. [11] estimated the personal exposure and cancer risk of Hispanic and white adults to 12 VOCs and carbonyls. Cumulative cancer risks were dominated by formaldehyde and paradichlorobenzene and, to a lesser extent, by acetaldehyde, chloroform, and benzene. Exposure to all of these compounds except benzene was primarily due to indoor residential sources. Cancer risks for pollutants emitted indoors were higher in houses with lower ventilation rates, particularly for paradichlorobenzene and chloroform. Risk estimates among the top 10th percentile of Hispanics were greater than 1 in 1,000. Formaldehyde was the largest contributor to cancer risks for 88% of whites and 69% of Hispanics. The authors suggested that both reductions in indoor sources and improved ventilation would reduce exposures.
• Logue et al. [12] conducted a hazard assessment of chemical air contaminants measured in residences. They summarized results from 77 published studies reporting chemical pollutant measurements in residences in the U.S. and countries with similar lifestyles.  Fifteen pollutants appeared to exceed chronic health standards (which are often based on cancer risk) in a large fraction of homes, and nine other pollutants were identified as potential chronic health hazards in a substantial minority (5-50%) of homes. Pollutants identified as priority hazards, based on the robustness of measured concentration data and the fraction of residences that appear to be impacted, included several VOCs – acetaldehyde, acrolein, benzene, 1,3 butadiene, 1,4-dichlorobenzene, formaldehyde, naphthalene [12].      
• Chan et al. [13] modeled the risks of cancer from exposures to VOCs in U.S. schools. The estimated cancer risks of VOCs in schools were low, about 10 per million occupants, which is less than the risk of cancer predicted for exposures to VOCs in homes.

1.         Loh, M.M., et al., Ranking cancer risks of organic hazardous air pollutants in the United States. Environ Health Perspect, 2007. 115(8): p. 1160-8. https://dx.doi.org/10.1289/ehp.9884.

2.         U.S. Environmental Protection Agency. Integrated risk information system. 2005  [cited 2013 August 6]; Available from: http://www.epa.gov/iris/.

3.         California Environmental Protection Agency. Part II. Technical support document for describing available cancer potency factors. 2005  [cited 2013 August 6]; Available from: http://www.oehha.ca.gov/air/hot_spots/pdf/May2005Hotspots.pdf.

4.         Wallace, L.A., Chapter 33. Assessing human exposure to volatile organic compounds., in Indoor Air Quality Handbook, J.D. Spengler, J.M. Samet, and J.F. McCarthy, Editors. 2000, McGraw Hill: New York. p. 33.1-33.35.

5.         Sax, S.N., et al., A cancer risk assessment of inner-city teenagers living in New York City and Los Angeles. Environ Health Perspect, 2006. 114(10): p. 1558-66.

6.         Sarigiannis, D.A., et al., Exposure to major volatile organic compounds and carbonyls in European indoor environments and associated health risk. Environ Int, 2011. 37(4): p. 743-65. https://dx.doi.org/10.1016/j.envint.2011.01.005.

7.         Batterman, S., et al., Sources, concentrations, and risks of naphthalene in indoor and outdoor air. Indoor Air, 2012. 22(4): p. 266-78. https://dx.doi.org/10.1111/j.1600-0668.2011.00760.x.

8.         Chin, J.-Y., et al., Concentrations and risks of p-dichlorobenzene in indoor and outdoor air. Indoor Air, 2013. 23(1): p. 40-49. https://dx.doi.org/10.1111/j.1600-0668.2012.00796.x.

9.         Sofuoglu, S.C., et al., An assessment of indoor air concentrations and health risks of volatile organic compounds in three primary schools. Int J Hyg Environ Health, 2011. 214(1): p. 36-46. https://dx.doi.org/10.1016/j.ijheh.2010.08.008.

10.       Zhou, J., et al., Health risk assessment of personal inhalation exposure to volatile organic compounds in Tianjin, China. Sci Total Environ, 2011. 409(3): p. 452-9. https://dx.doi.org/10.1016/j.scitotenv.2010.10.022.

11.       Hun, D.E., et al., Cancer risk disparities between Hispanic and non-Hispanic white populations: the role of exposure to indoor air pollution. Environmental health perspectives, 2009. 117(12): p. 1925. https://dx.doi.org/10.1289/ehp.0900925.

12.       Logue, J.M., et al., Hazard assessment of chemical air contaminants measured in residences. Indoor Air, 2012. 21(2): p. 92-109. https://dx.doi.org/10.1111/j.1600-0668.2010.00683.x.

13.       Chan, W.R., et al., Estimated effect of ventilation and filtration on chronic health risks in U.S. offices, schools, and retail stores. Indoor Air, 2015. 26(2): p. 331-343. https://dx.doi.org/10.1111/ina.12189.

 

Additional cancer studies specific to formaldehyde

Potential cancer risks from formaldehyde have received substantial attention. In 1996 and again in 2006, the International Agency for Research on Cancer (IARC) of the World Health Organization concluded that formaldehyde was a human carcinogen [1]. The primary evidence supporting this conclusion was increases in cancer in workers exposed to formaldehyde concentrations exceeding the concentrations present in most non-occupational indoor environments. The formaldehyde concentrations necessary to cause cancer were not specified by the IARC; however, the committee's conclusions were based primarily on studies of industrial exposures to formaldehyde with concentrations of 500 ppb or higher. The study cited by the IARC as "most informative" found that cancer risks were primarily associated with time-average workplace concentrations greater than 500 ppb and peak workplace concentrations greater than 2000 ppb [2]. In 2009, IARC updated its conclusions based on additional evidence, and concluded that formaldehyde was a cause of not only nasopharyngeal cancer, but also of leukemia, in humans [3]. Based on the epidemiologic evidence, this addition was supported by Zhang et al. [4] and Zhang et al. [5], but in contrast, Checkoway et al. [6] found no consistent or strong epidemiologic evidence that formaldehyde was causally related to leukemia or lymphatic cell cancers. 

Considerable attention has also been devoted to quantifying the cancer risks from inhalation of formaldehyde, and the estimated risk varies widely. EPA's Integrated Risk Information System [7] provides an estimated cancer risk of one in 10,000 from lifetime exposure at a concentration of 7 ppb. Risks are assumed to vary in direct proportion to concentration. Specific cancer-related guidelines for formaldehyde are provided in Table 4. In contrast, the World Health Organization, based on recommendations of a committee of experts, published in 2010 a recommended guideline level of 100 ppb formaldehyde as protective against eye and nasal irritation and also all long-term effects including cancer and reproductive and developmental toxicity [8]. This was supported by a review by Nielsen and Wolkoff [9]. Nielsen et al. [10] reviewed later evidence and concluded that this evidence strengthened the support for this WHO guideline.  The Occupational Safety and Health Administration (OSHA) has a guideline for formaldehyde and cancer of 750 ppb as an 8-hour time-weighted average, but no established guideline for longer exposures. 

Liteplo and Meek [11] reviewed the evidence on cancer risk of formaldehyde based on airborne concentrations. Their review was based heavily on laboratory studies of how formaldehyde affected cell proliferation in animals. They concluded that the risks to the general population of respiratory tract cancers from formaldehyde are "exceedingly low" for concentrations less than 80 ppb. As discussed above, typical indoor formaldehyde concentrations are significantly less than 80 ppb. While the authors do not precisely quantify the term "exceedingly low", they refer to a risk estimate of approximately three in one hundred million. Another recent paper used sophisticated models of exposures and of cancer induction mechanisms to predict the risks of respiratory tract cancer from exposures to formaldehyde [12]. For non-smokers, the predicted risk of cancer with an 80-year exposure to a formaldehyde concentration of 30 ppb was one in ten million to 30 in one million depending on the model used to relate cancer dose with risk. For smokers, the corresponding risk estimates were approximately one in one million to 500 in one million.

1.         World Health Organization International Agency for Research on Cancer, IARC monographs on the evaluation of carcinogenic risks to humans. Volume 88 formaldehyde, 2-butoxyethanol, 1-tert-butoxypropan-2-ol. Summary of data reported and evaluation. 2006, World Health Organization Available from: http://monographs.iarc.fr/ENG/Monographs/vol88/volume88.pdf.

2.         Hauptmann, M., et al., Mortality from solid cancers among workers in formaldehyde industries. Am J Epidemiol, 2004. 159(12): p. 1117-30.

3.         IARC. Formaldehyde. IARC Monographs on the Evaluation of Carcinogens 2009  [cited 2013 August 15]; Available   here.

4.         Zhang, L., et al., Formaldehyde and leukemia: epidemiology, potential mechanisms, and implications for risk assessment. Environmental and Molecular Mutagenesis, 2010. 51(3): p. 181-191. https://dx.doi.org/10.1002/em.20534.

5.         Zhang, L., et al., Formaldehyde exposure and leukemia: a new meta-analysis and potential mechanisms. Mutation Research/Reviews in Mutation Research, 2009. 681(2): p. 150-168. https://dx.doi.org/10.1016/j.mrrev.2008.07.002.

6.         Checkoway, H., et al., Critical review and synthesis of the epidemiologic evidence on formaldehyde exposure and risk of leukemia and other lymphohematopoietic malignancies. Cancer Causes & Control, 2012. 23(11): p. 1747-1766. https://dx.doi.org/10.1007/s10552-012-0055-2.

7.         U.S. Environmental Protection Agency. Integrated risk information system. 2005  [cited 2013 August 6]; Available from: http://www.epa.gov/iris/.

8.         World Health Organization Regional Office for Europe, WHO Guidelines for Indoor Air Quality: Selected Pollutants WHO Guidelines for Indoor Air Quality. 2010, Bonn, Germany.

9.         Nielsen, G.D.r. and P. Wolkoff, Cancer effects of formaldehyde: a proposal for an indoor air guideline value. Archives of toxicology. 84(6): p. 423-446.

10.       Nielsen, G.D., S.T. Larsen, and P. Wolkoff, Recent trend in risk assessment of formaldehyde exposures from indoor air. Archives of toxicology, 2013. 87(1): p. 73-98. https://dx.doi.org/10.1007/s00204-012-0975-3.

11.       Liteplo, R.G. and M.E. Meek, Inhaled formaldehyde: exposure estimation, hazard characterization, and exposure-response analysis. J Toxicol Environ Health B Crit Rev, 2003. 6(1): p. 85-114.

12.       Conolly, R.B., et al., Human respiratory tract cancer risks of inhaled formaldehyde: dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset. Toxicol Sci, 2004. 82(1): p. 279-96.