Indian Journal of Occupational and Environmental Medicine Medknow Publications ISSN: 0973-2284 EISSN: 1998-3670 Vol. 10, Num. 3, 2006, pp. 111-115

Indian Journal of Occupational and Environmental Medicine, Vol. 10, No. 3, September-December, 2006, pp. 111-115

Review Article

Phthalate exposure and health outcomes

Rastogi SK, Kesavachandran C, Mahdi Farzana, Pandey Amit

Era's Lucknow Medical College and Hospital, Lucknow
Correspondence Address:Department of Physiology, Era's Lucknow Medical College and Hospital, Lucknow Email: subhodhrastogi@yahoo.com

Code Number: oe06027

Abstract

Keywords: Exposure, human, phthalate

Introduction

Phthalates represent a large class of chemicals that are widely used in commercial products. Phthalates are dialkyl or alkyl /aryl esters of 1,2-benzene dicarboxylic acids which have numerous uses as softeners of plastics, solvents in perfumes and additives to hair sprays, lubricants and insect repellents.[1],[2],[3],[4],[5] In the residential construction or automotive industries diethyl hexyl phthalate, dibutyl phthalate and butyl benzyl phthalate are used in floorings, paints, adhesives, wood finishes, wall paper and in PVC products. The high levels of mono ethyl phthalates across the population are most likely associated with the every day use of consumer products that commonly contain diethyl phthalates (DEP), such as detergents, soaps, cosmetics, shampoo and perfumes. Phthaltes are multifunctional chemicals used to hold colour and scent in consumer and personal care products. Phthalates are also present in drinking water, air and food. Diethyl hexyl phthalate (DEHP), one of the more commonly used phthalates leaches from blood products, intravenous and dialysate bags and tubings made with PVC.

In particular di - (2-ethylhexyl) phthalate (DEHP) is the most commonly used plasticizer. Globally, more than 18 billion pounds of phthalates are used each year and well above 2 million tons of DEHP alone are produced annually worldwide.[6] Other important phthaltes production and application wise are DEP, dibutyl phthalate (DBP), di- iso - and di-n-butylphthalate (DiBuP, DnBuP), butyl-benzylphthalate (BBzP),di-isononylphthalte (DiNP) or di-n-octylphthalte (DnOP).[7] The potential for non occupational exposure to phthaltes is high given their use in a vast range of consumable products and because they are not covalently bound to the other chemicals in the formulations. After exposure, phthalates are rapidly hydrolyzed to their respective monoesters which can be further biotransformed to oxidative metabolites.

The wide spread use of phthalates results in multiple human exposure routes. Humans are exposed to these compounds through ingestion, inhalation and dermal exposure for their whole lifetime, since the intrauterine life.[8],[9],[10] Dermal and inhalative exposures are considered to be the major route of exposure to DEP that is found in hygiene products such as soap, shampoo and conditioners. DEP and DBP are used extensively in products with volatile components such as perfumes, nail polishes and hair sprays possibly leading to inhalation and efficient absorption through the lungs. Dermal absorption also occurs at a significant rate for phthalates with short side chains such as DEP, DBP and BzBP.[11] In contrast, for phthalates that are used mainly as plasticizers, such as DEHP, oral exposures predominate.[12]

Metabolism of phthalates

Urinary measures of phthalates

Health outcomes

Respiratory effects

Reproductive toxicity

Evidence of population exposed to phthalates as well as in vitro studies suggest that some phthalates are normally active. The animal studies showed association between some phthalates and testicular toxicity. The National Institute of Occupational Safety and Health has classified DBP as a high priority chemical for study because of its widespread use and its reproductive toxicity. It is toxic to the testes, possibly through its metabolite, MBP.[29] Of the phthalate most commonly used, DEHP and DBP and their metabolites have the greatest potential for toxicity. DEHP has been reported to suppress the estradiol and ovulation in cycling rats. It is a reproductive toxicant and is carcinogenic in animal models. The phthalates have been also shown to cause endocrine disruption causing testicular toxicity, decreased fertility, decreased sperm motility and decreased milk synthesis. Several phthalates viz, DEHP, DBP and BZP are teratogenic in animals.[30],[31] Animal toxicology of several phthalates have been studied. DEHP is a rodent liver carcinogen through a mechanism thought to involve peroxisome proliferation.[32] However, carcinogenicity by this mechanism is unlikely to be relevant to humans.[33]

Several phthalates and their metabolic products have been shown to be developmental and reproductive toxicants affecting particularly male reproductive development[34],[35],[36],[37] and are suspected of having endocrine disrupting or modulating effects.[38] An endocrine disruptor is a chemical with the potential to alter hormone action within the body.[39] Thus these chemicals have been found to interfere with the function of endocrine system which is responsible for growth, sexual development and many other essential physiological functions both in males and females.[40],[41]
Gestational and lactational exposures to large doses of DBP and its metabolite MBP in rats cause male reproductive tract malformation.[36] DBP reduces the production of testosterone by fetal testis through an antiandrogenic mechanism.[42] The active testicular toxicant may be DEHP metabolite MEHP.[43],[44]

Developmental toxicity

Results from animal toxicology studies have demonstrated endocrine modulating effects from phthalate exposure.[31] For example DEHP alters thyroid structure and activity in male wistar rats and produces reproductive and developmental toxicities in rodents.[45] In male rodents, the testes are a primary target tissue and exposure to high doses of DEHP results in decreased testicular weights and tubular atrophy.[4] DEHP is a known reproductive and developmental toxicant in animals exerting its toxicity already in utero. Some effects are malformed reproductive organs, a decreased anogenital distance, retained nipples at birth, a general decrease in mating, pregnancy or fertility, reduced prenatal and post natal survival of the offspring, reduced sperm counts or reduced reproductive organ weights.[45] DEHP is known to produce decreased testicular weight,[46] severe testicular atrophy and reduced weight of sex organs in adult male rats by a mechanism thought to involve decreased fetal testosterone synthesis during male sexual differentiation.[35]

Some phthalates and their metabolites act functionally as antiandrogens during the pre natal period[35],[47],[48] and cause reproductive and developmental toxicity in animals especially in males. Some developmental effects include reduction in androgen dependent tissues (Seminal vesicles, epididymis, prostate.[38],[49],[50]

Endocrine disruptors

Genotoxicity

Recent in vitro studies using the alkaline comet assay (single cell gel electrophoresis) found di-n-butyl phthalate (DBP) and di-isobutyl phthalate (DiBP) to be genotoxic in human epithelial cells of the upper aerodigestive tract[60] as well as in mucosal cells and lymphocytes.[61] Additionally, the comet assay was used to detect DNA damage in human lymphocytes induced by in vitro exposure to DEHP and MEHP.[62] Using the alkaline comet assay, researchers have found evidence of genotoxicity with in vitro studies examining lymphocytes and mucosal cells of digestive tract after exposure to DBP and DiBP.

In another study using the alkaline comet assay on human leucocytes, an association between MEHP and DEHP and increased tail movements was found.[60],[61],[62]

References

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