Mechanistic considerations for human relevance of cancer hazard of di(2-ethylhexyl) phthalate

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a peroxisome proliferator agent that is widely used as a plasticizer to soften polyvinylchloride plastics and non-polymers. Both occupational (e.g., by inhalation during its manufacture and use as a plasticizer of polyvinylchloride) and environmental (medical devices, contamination of food, or intake from air, water and soil) routes of exposure to DEHP are of concern for human health. There is sufficient evidence for carcinogenicity of DEHP in the liver in both rats and mice; however, there is little epidemiological evidence on possible associations between exposure to DEHP and liver cancer in humans. Data are available to suggest that liver is not the only target tissue for DEHP-associated toxicity and carcinogenicity in both humans and rodents. The debate regarding human relevance of the findings in rats or mice has been informed by studies on the mechanisms of carcinogenesis of the peroxisome proliferator class of chemicals, including DEHP. Important additional mechanistic information became available in the past decade, including, but not limited to, sub-acute, sub-chronic and chronic studies with DEHP in peroxisome proliferator-activated receptor (PPAR) α-null mice, as well as experiments utilizing several transgenic mouse lines. Activation of PPARα and the subsequent downstream events mediated by this transcription factor represent an important mechanism of action for DEHP in rats and mice. However, additional data from animal models and studies in humans exposed to DEHP from the environment suggest that multiple molecular signals and pathways in several cell types in the liver, rather than a single molecular event, contribute to the cancer in rats and mice. In addition, the toxic and carcinogenic effects of DEHP are not limited to liver. The International Agency for Research on Cancer working group concluded that the human relevance of the molecular events leading to cancer elicited by DEHP in several target tissues (e.g., liver and testis) in rats and mice can not be ruled out and DEHP was classified as possibly carcinogenic to humans (Group 2B).

Reproductive and developmental effects of phthalate diesters in females

“…PPARα is thought to be at least partially responsible for toxicity in rodents, particularly in the liver. However, the human PPARα has lower affinity for phthalates and is expressed at a lower level (Ito & Nakajima, 2008; Rusyn & Corton, 2011). As a result, the consequences of phthalate exposure in rats may be due to mechanisms that are not applicable in humans.…”

A systematic approach for identifying and presenting mechanistic evidence in human health assessments

“…Based on a survey of seven recent and/or highly cited reviews from diverse (in terms of affiliation with the government, academia and/or industry sectors) authorship (Caldwell, 2012; Guyton et al, 2009; Klaunig et al, 2003; Peters et al, 2005; Roberts et al, 2007; Rusyn and Corton, 2012; Rusyn et al, 2006, Melnick, 2001; McKee, 2000) nine mechanistic events for DEHP in liver were identified (Figure 2). These were peroxisome proliferation, cell proliferation, PPAR receptor activation, oxidative stress, nuclear receptor activation, genotoxicity, apoptosis, disruption of gap junction intercellular communication, and Kupffer cell activation.…”

“…For this work, we constructed a comprehensive list of likely potential mechanisms of DEHP-induced liver carcinogenesis from reviews on the mechanisms of DEHP liver effects published by a diverse author set (Caldwell, 2012; Guyton et al, 2009; Klaunig et al, 2003; Peters et al, 2005; Roberts et al, 2007; Rusyn and Corton, 2012; Rusyn et al, 2006; Melnick, 2001; McKee, 2000). We considered reviews published since the release of the 2000 IARC monograph on DEHP (IARC, 2000), and selected recent, as well as highly cited older publications.…”

Epigenetic Effects of Endocrine Disrupting Chemicals: Phthalates: Review

“…B Ba aş şl la at tı ıl lm mı ış ş H Hü üc cr re el le er rd de e K Kl lo on na al l B Bü üy yü üm me en ni in n A Ar rt tı ış şı ı: : Peroksizom proliferatörleri tarafından indüklenen oksidatif stres ve diğer endojen faktörler (replikasyon hataları, normal oksidatif metabolizma gibi), kemirici karaciğerinde hücre proliferasyonundaki artış, apoptozun baskılanması ve bunu izleyen olaylara neden olur. 22,23 Bu durumda kemirici hepatositlerinde ortaya çıkan genetik ve epigenetik değişiklikler sonucu başlatılmış hücre-Turkiye Klinikleri J Pharm Sci 2016;5 (2) lerde klonal artış görülür. Bu artış, DEHP ve diğer peroksizom proliferatörlerinin "tümör geliştirici-ler" olarak sınıflandırılmasını beraberinde getirmiştir.…”