Diverse developmental toxicity of di-n-butyl phthalate in both sexes of rat offspring after maternal exposure during the period from late gestation through lactation

Lee, Kyoung-Youl; Shibutani, Makoto; Takagi, Hironori; Kato, Natsumi; Takigami, Shu; Uneyama, Chikako; Hirose, Masao

doi:10.1016/j.tox.2004.06.013

Cited by 124 publications

(107 citation statements)

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“…DnBP and BBzP produce a number of reproductive abnormalities like malformations of the epididymis and the external genitalia (hypospadias), undescended testicles (cryptorchidism), impaired spermatogenesis and a general reduction of male fertility (Wine et al, 1997;Mylchreest et al, 2000). DnBP and BBzP cause signs of feminization (retention of nipples/areolae in male rodents) and a reduced anogenital distance (AGD) as a first indication of general demasculinization (Lee et al, 2004;Tyl et al, 2004;Foster, 2006). On a cellular level, both phthalates lead to decreased fetal testicular levels of testosterone and insulinlike factor 3 (Insl3) and to increased serum levels of the follicle-stimulating hormone (FSH) (Nagao et al, 2000;Wilson et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…An evaluation by the European Food Safety Authority (EFSA) in 2005 allocated a Tolerable Daily Intake (TDI) for DnBP of 10 mg/kg bw/day based on the end points impairment of germ cell development and structural changes in the mammary gland (Lee et al, 2004;EFSA, 2005a). The TDI for BBzP was set at 500 mg/kg bw/day based on the end points testicular toxicity and reduction of the AGD (Tyl et al, 2004;EFSA, 2005b).…”

Section: Introductionmentioning

confidence: 99%

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Di-n-butylphthalate and butylbenzylphthalate — urinary metabolite levels and estimated daily intakes: pilot study for the German Environmental Survey on children

Koch

Becker

Wittassek

et al. 2006

J Expo Sci Environ Epidemiol

138

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We analysed urine samples from the 2001/2002 pilot study of the German Environmental Survey on Children (GerES IV) for the concentrations of the di-n-butylphthalate (DnBP) metabolite mono-n-butylphthalate (MnBP) and the butlybenzylphthalate (BBzP) metabolite mono-benzyl-phthalate (MBzP). The study population consisted of 239 children (106 boys, 133 girls) aged between 2 and 14 years (median 8.5 years). We applied two calculation models to estimate the daily intake for the two parent phthalates from metabolite excretion. One was based on the creatinine-related metabolite concentrations; the other was based on the volume-related metabolite concentrations. Median urinary metabolite concentrations were 174 mg/l (136 mg/g creatinine) for MnBP and 19.7 mg/l (15.3 mg/g creatinine) for MBzP. Such levels have been determined in German children before. Compared to the USA, German median MnBP levels were about 3-10 times higher, whereas MBzP levels were in the same range. Median daily intakes calculated with the creatinine-based model were 4.07 (range: 0.66-76.4; 95th percentile: 14.9) mg/kg body weight (bw)/day for DnBP and 0.42 (range: 0.06-13.9; 95th percentile: 2.57) mg/kg bw/day for BBzP. Daily intakes calculated with the volume-based model were approximately two times higher with a median of 7.61 (range: 0.91-110; 95th percentile: 30.5) mg/kg bw/day for DnBP and a median of 0.77 (range: 0.05-31.3; 95th percentile: 4.48) mg/kg bw/day for BBzP. Using the creatinine model, 28 (11.7%) of the 239 children exceeded the TDI for DnBP of 10 mg/kg bw/day defined by the European Union. Employing the volume model, 89 (37.2%) children exceeded the TDI. For BBzP, no preventive limit values (TDI or RfD) were exceeded. For both phthalates and independent of the model, we found increasing daily intakes with decreasing age. Between 25% (creatinine model) and 50% (volume model) of the 2-4-year old children had daily intakes for DnBP above the TDI.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Di-n-butylphthalate and butylbenzylphthalate — urinary metabolite levels and estimated daily intakes: pilot study for the German Environmental Survey on children

Koch

Becker

Wittassek

et al. 2006

J Expo Sci Environ Epidemiol

138

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“…Giant cell formation was often a feature associated with loss of germ cells (31). DIBP in high dose group caused complete loss of germ cells in testis.…”

Section: Discussionmentioning

confidence: 97%

“…On one hand, it has been shown that DIBP causes loss of germ cells, detaches the germ cells from basement membrane which ultimately would result in impending loss in experimental testis (3,11,31).…”

Section: Discussionmentioning

confidence: 99%

Ovarian development in Wistar rat treated prenatally with single dose diisobutyl phthalate

Ray¹,

D’Souza²,

Kumar³

et al. 2013

BLL

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Abstract:Phthalates are a class of industrial compounds with an array of toxicological properties used in day to day life. Diisobutyl phthalate on (DIBP) is used as an additive to keep the plastics soft or fl exible (plasticizer) in nitrocellulose plastic, nail polish, explosives, lacquer manufacturing etc. Although DIBP exposure in humans is generally low, people in adhesive industries and pharmaceutical industries are exposed to higher levels. The aim of this study was to determine the effect of single dose of DIBP on developing ovary of Wistar rat. One hundred and eight adult pregnant Wistar rats were divided into control and experimental groups. Rats in experimental group were given DIBP on day 10, 12 and 14 of gestation at 0.375, 0.75 and 1.25 ml/kg body weight dose intraperitoneally in a single dose. Sections of ovaries collected on day 21 of gestation were stained with hematoxylin and eosin and examined and Masson's trichrome histologically. Sections belonging to the control group showed the presence of oocytes in clusters separated by thin fi brous septa. Degeneration oocytes, empty follicles surrounded by follicular cells without gonocytes in the center were observed in ovarian stroma. Blood vessels in the ovarian stroma were prominent and congested. Around a bunch of follicles total architectural disarray was observed although on special staining fi brosis was not evident. As pregnant women are constantly exposed, effect of DIBP on ovary of a developing fetus would denote the long term consequence in future generations (Fig. 5, Ref. 39 Phthalates are a class of widely used industrial compounds known technically as dialkyl or alkyl aryl esters of 1, 2-benzenedicarboxylic acid. The common forms of phthalates are Diethyl hexyl phthalate (DHEP), Diallyl phthalates (DAP), Di-n-propyl phthalates (DPP), Di-n-butyl phthalates (DBP), and Diisobutyl phthalates (DIBP).Phthalates with a variety of toxicological properties are used in day to day life. These phthalates are nearly omnipresent in modern society and are found in the plastic items, vinyl fl ooring, wall coverings, lubricants, adhesives, detergents, nail polish, hair spray and car wash (1).The adverse effects produced by phthalates are changes in morphology, physiology, growth, development or life span of an organism which results in an impairment of functional capacity and ability to compensate for additional stress (2). Diisobutyl phthalateDIBP (phthalic acid ,di isobutyl ester 1,2-benzenedicarboxylic acid ,bis-(2-methyl propyl) ester di-(isobutyl)-1,2-benzene dicarboxylate) is the branched isomer of DBP and an additive used to keep the plastics soft or more fl exible (plasticizer) often in combination with other phthalates. DIBP is used in nitrocellulose plastic, nail polish, explosive materials, lacquer manufacturing, consumer products, blood bags, pharmaceuticals and automobile parts. They are ubiquitous in our environment and most people including pregnant women and their fetuses are exposed to multiple phthalates at a time. Saillenfait et al estim...

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“…Similarly, while existing protocols may allow for the measurement of a number of endogenous hormones, such measurements are not always undertaken, or the results may be confounded by stress or the inconsistency of diurnal variations. Test protocols may also allow for relevant tissues to be examined, but not in a way that might reveal subtle changes, such as effects on the weight of the thyroid (as for the updated TG 407), and also for example for the weight of (subdivisions of) the prostate gland, or histological effects on mammary gland development that are only visible at the microscopic level, which have been reported following treatment with bisphenol A and dibutyl phthalate respectively (Welshons et al, 1999;Vom Saal and Myers, 2010;Lee et al, 2004). It is because of the inconsistency in some of these measurements, revealed by inter-laboratory validation studies, that they are not obligatory in standard test protocols.…”

Section: Adequacy Of Current Test Protocolsmentioning

confidence: 99%

Scientific report of the Endocrine Active Substances Task Force

2010

EFSA Journal

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Discussions within the Scientific Committee and the Advisory Forum have called for the development of a common approach within EFSA towards endocrine active substances. The aim of this report by an internal EFSA task force is to clarify the state-of-play, and provide recommendations for scientific and communication issues. Both specific issues and new regulations make it necessary to follow up on recent developments with the EU bodies, Member States, and internationally, in order to avoid diverging assessment approaches and the duplication of work. The proposed actions for EFSA are to contribute to the work in progress under the auspices of DG Environment and to continue its participation in the ongoing OECD activities in the area of testing of chemicals. The development of a generally accepted risk assessment methodology is an additional challenge due to the complexity of the issues involved. Here, the task force recommends that EFSA continues its activities aimed at developing harmonised methodologies for risk assessment of combined exposures to endocrine active substances in food. EFSA should continue to build a dialogue to develop a common strategy with the EC, other EU bodies, Member States' Competent Authorities, international organisations and partners, as well as external experts and stakeholders on the before mentioned issues. In line with these recommendations, it is proposed that EFSA creates a working group of Panel experts and national experts to advise on prioritising the work on endocrine active substances. EFSA should also work with the experts in its Advisory Group on Risk Communications in conjunction with the communication experts from Member States, and continues to monitor and analyse media and stakeholder developments, in order to define a strategy for communications addressing both the collective group and specific endocrine active substances. © European Food Safety Authority, 2010 KEY WORDSEndocrine active substances, endocrine disrupters, hazard identification, risk assessment, method harmonisation, common strategy, risk communication SUMMARYThe issue of endocrine active substances touches upon the activities of several of the EFSA Units and Panels, recent examples being the risk assessment of bisphenol A, the hazard assessment of isoflavones and the implementation of the new regulation on plant protection products. Previous examples include contaminants like organotins, dioxins, PCBs, and hormone residues.Discussions within the Scientific Committee and the Advisory Forum have called for the development of a common approach within EFSA towards endocrine active substances. A first step in this process was to appoint a task force to identify trends and developments in the assessment of the health risks and risk communication issues EFSA may have to address. The aim of this report by the task force is to clarify the state-of-play, and provide recommendations for the scientific and communication issues.Current activities and developments within EFSA, European Commission, other Europ...

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Diverse developmental toxicity of di-n-butyl phthalate in both sexes of rat offspring after maternal exposure during the period from late gestation through lactation

Cited by 124 publications

References 30 publications

Di-n-butylphthalate and butylbenzylphthalate — urinary metabolite levels and estimated daily intakes: pilot study for the German Environmental Survey on children

Di-n-butylphthalate and butylbenzylphthalate — urinary metabolite levels and estimated daily intakes: pilot study for the German Environmental Survey on children

Ovarian development in Wistar rat treated prenatally with single dose diisobutyl phthalate

Scientific report of the Endocrine Active Substances Task Force

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