Identification of Research Needs to Resolve the Carcinogenicity of High-priority IARC Carcinogens. Views and Expert Opinions of an IARC/NORA Expert Group Meeting, Lyon, France, 30 June - 2 July 2009. IARC Technical Publication No. 42. Lyon, France: International Agency for Research on Cancer, 2010 Jul; 42:183-195
DEHP is commonly used in PVC and other plastics. Epidemiologic studies have been performed for a Swedish PVC-processing factory (Hagmar et al., 1990; Hardell et al., 2004), a mortality study of U.S. workers in a plastics manufacturing and research and development plant (Selenskas et al., 1995), and a population-based case-control study among Danish men (Heineman et al., 1992) exposed to PVC and phthalates. Now that specific biomarkers of exposures for DEHP exist, these work populations identified above may serve as potential future DEHP biomarker epidemiological studies in addition to cohorts defined by Gaudin et al. (2008) and Hines et al. (2009). Also, in future biomarker epidemiological studies it would be necessary to identify what phthalates are used in the workplace and only count these metabolites as occupational exposure. DEHP metabolites should be determined in pre- and post-shift urine samples because an increase over the workday would indicate occupational exposures, and a decrease a non-occupational exposure. In occupational and environmental settings, DEHP is often accompanied by other phthalates (i.e., to get the optimal flexibility in plastics a combination of phthalates are often used). Given that other phthalates may have similar carcinogenic properties; a cumulative phthalate exposure index should be used in future epidemiological studies. The outcome variable could be cancer incidence, mortality, but preference would be to use an effect biomarker such as 8-OHdG with the exposure biomarkers may be useful (see section on oxidative stress). In terms of human data, another suggested research need would be to look at studies of testicular germ cell cancer. DEHP causes reproductive effects (testicular dysgenesis, Leydigcell dysfunction, cryptorchidism, and hypospadias) in male rodents, which are similar to risk factors for testicular germ cell cancer in humans. Furthermore, chemical-specific data to define the range of effects that may contribute to human carcinogenesis are insufficient, and other modes, mechanisms, toxicity pathways and molecular targets may contribute to or be required for the observed adverse effects. Similarly, the epidemiologic data are inadequate to inform conclusions of human relevance of peroxisome proliferators as a class (Guyton et al., 2009). Future toxicological studies: Previously, there have not been no reports concerning the effects of exposure of DEHP to transgenic mice with hPPARalpha(TetOff) or hPPARalpha(PAC) , but Ito and Nakajima (2008) reported that at a relatively high dose of DEHP (5.0 mmol/kg for 2 weeks) PPARalpha was activated in the liver of both genotyped mice. Although the magnitude of response was not large in hPPARalpha(TetOff) mice from the standpoint of the target gene expression in the liver, the induction was beyond doubt. Hurst and Waxman (2003) reported a 5-fold lower sensitivity to the DEHP metabolite MEHP of human compared with mouse PPAR (see discussions in Guyton et al., 2009 regarding receptor activation). The results from the typical peroxisome proliferator, Wy-14643, may not always be similar to those of DEHP: Future studies are needed using hPPARalpha(TetOff), which expresses the human receptor only in liver, or hPPARalpha(PAC), which expresses the human receptor not only in liver but also in kidney, heart, intestine and brown adipose tissues, mouse models to elucidate the role of human PPARalpha in DEHP carcinogenesis. Further characterization of DEHP exposures in industry is needed in order to reduce exposure misclassification in epidemiological studies. Since no epidemiologic studies have been published since the last Monograph (IARC, 2000) it is encouraged to use already established cohorts in the PVC-processing factories.
Cancer; Carcinogens; Carcinogenesis; Carcinogenicity; Plastics; Plastics-industry; Biomarkers; Blood-samples; Blood-sampling; Blood-cells; Blood-analysis; Epidemiology; Mortality-data; Mortality-rates; Mortality-surveys; Reproductive-system-disorders; Reproductive-effects; Laboratory-animals; Animal-studies; Animals
Identification of Research Needs to Resolve the Carcinogenicity of High-priority IARC Carcinogens. Views and Expert Opinions of an IARC/NORA Expert Group Meeting, Lyon, France, 30 June - 2 July 2009, IARC Technical Publication No. 42