Combined Actions and Interactions of Chemicals in Mixtures

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Table 7.4.1.1 Overview of in vivo tests for reproductive toxicity testing Test Exposure period Endpoints in offspring Guideline(s) Generation studies Continuously over one, Growth, development and viability OECD TG 415 One- two or several genera- Histopathology of sex organs, brain and generation Study tions target organs OECD TG 416 Two- Fertility Proposal: oestrus cyclicity and sperm quality generation Study Prenatal Developmental Toxicity Study (Teratology study) Developmental Neurotoxicity Study (Behavioral teratology studies) Reproduction/ Developmental toxicity screening test 104 Usually during organogenesis Proposal: from implantation to the day before birth During pregnancy and lactation At least three dose levels from 2 weeks prior to mating until day 4 postnatal Modified from Hass et al 1994 Resorptions Fetal growth Morphological variations and malformations. Birth and pregnancy length Physical and functional maturation Behavioral changes due to CNS and PNS effects Brain weights and neuropathology Fertility Pregnancy length and birth Foetal and pup growth and survival until day 3 OECD TG 414 OECD TG 426 Developmental Neurotoxicity Study (draft 1999) OECD TG 421 and 422 This chapter illustrates the consequences of exposure to chemical mixtures on reproduction based upon essential, relevant publications and as such it should not be considered as a bibliographic review of the subject. Concerning the effects presented above, the literature search does not consider congenital cancer and behavioural effects, including sexual behaviour. The main focus is on examples of interactions in vivo. However, a brief introduction of in vitro techniques used in the study of reproductive effects is included. One group of potential reproductive and developmental toxicants, the endocrine disrupting chemicals (EDCs) are considered in the next chapter (7.5.1) because exposure to such compounds may also affect other targets than the reproductive system. 7.4.2 In vitro studies for testing interaction of teratogenic compounds During the last 30 years more than 20 in vitro test systems have been used in the study of teratogenic effects. They can be divided into two categories, based on the involvement of morphogenesis. Morphogenetic tests are based on the use of isolated embryos, organs or regenerating tissues, whereas non-morphogenetic tests are based on cell cultures. In general, morphogenetic tests are sensitive and provide information on the effects on the morphology of the foetus. However, the test protocols are complex and not well suited for screening large numbers of chemicals. In general, the results of in vitro testing within the field of reproduction and development are difficult to interpret in terms of risk assessment due to the complex nature of these processes. Two individuals - the mother and foetus - are involved and effects on both have to be considered. In the maternal body, most chemicals are metabolised, and the foetus is protected to some extend by the placenta. However, with the exception of compounds with a very high molecular weight (over 600 dalton) or compounds, which are highly electronegative or electropositive, almost all chemical substances may pass from the mother’s circulation to that of the foetus. This means that in vitro studies can only indicate either a possible effect or lack of effect in the whole animal. This complexity is illustrated by studies on 5-fluoracil (5-FU). 5-FU is a known teratogen in the rat. It acts primarily by disrupting the balance of the intracellular nucleotide pools, leading to arrest of DNA synthesis and cell replication. In vitro
studies using leukaemic cells have shown that 5-FU toxicity could be ameliorated by nucleoside (thymidine or deoxycytidine) supplementation (Elstein et al. 1997). Other reports, too, have indicated a protective role of deoxyribonucleotides against this class of teratogens. However, an in vivo developmental study showed that supplementation of deoxycytidine and deoxyguonosine had no protective effect on 5-FU induced toxicity. On the contrary, the adverse effect of 5-FU was found to be potentiated (Lau et al. 1997). The developmental effect of combinations of methanol and formic acid was studied in 9-day-old rat embryos (Whole Embryo Culture, WBC). Methanol has shown teratogenicity in rodents, and in vitro studies have demonstrated that embryonic development was adversely affected under conditions where methanol was not metabolised to formate to any appreciable extent. After the embryotoxicity of the individual substances had been established in previous studies, concentrations of methanol and formate were chosen which would produce similar effects using the parameter “Developmental Score” (DEVSC), and isoboles were plotted joining the equivalently toxic doses. (Andrews et al. 1998). The results showed that low concentrations of formate together with various concentrations of methanol did not significantly change the DEVSC from that expected from methanol alone, while high concentrations of formate resulted in significant reductions of embryonic DEVSC. The authors suggest that the result was indicative of an antagonistic interaction. They cite a publication in which in vivo studies indicate that formate enters the metabolic pathway shared by it and 2-methoxyethanol (ME) or a metabolite of ME thereby rendering protection of the embryo as a result of a competitive inhibition. This could indicate that the interaction shown in the present in vitro study was a result of a complex dissimilar action. 7.4.3 Examples of interaction of reproductive toxicants in vivo The selection of chemical mixtures as they appear in the environment or in foods can be used as one approach to test chemical combinations in animal experiments. An alternative approach is to select chemical mixtures containing agents with equal target organ, similar modes of actions or similar chemical structure. In addition, therapeutic use of antidotes as protectors of known toxicants are well described. The first approach can be illustrated by a study on exposure of rodents to chemical mixtures representative of groundwater contamination (Heindel et al. 1994). The potential reproductive and developmental consequences of exposure to pesticides and fertilisers were evaluated during a continuous breeding study in CD-1 mice, and during a developmental study in pregnant Sprague-Dawley rats. The animals were exposed to two pesticide mixtures representing the groundwater contamination in California and Iowa at dose levels of 1, 10, and 100 times the concentrations of the pesticides in the water. No detectable reproductive, general or developmental toxicity of the pesticides mixtures was observed at any of the dose levels. The authors specified that the purpose of the study was to evaluate the health effects of realistic concentration of human exposure. Thus, the concentrations tested were probably considerably lower than the maximally tolerated doses. Consequently, the low but realistic doses used in this study did not induce any interaction or combined effect. In a 5x5x5 full-factorial design, three compounds, commonly found at hazardous waste sites, were combined using 5 dosages of each agent. Trichloroethylene (TCE), di-(2-ethylhexyl)phthalate (DEHP) and heptachlor (HEPT) were administered to rats by oral gavage from days 6-15 during gestation. The selection of dose levels was based on data from single-agent studies, and linear regression 105
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Combined Actions and Interactions o
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Contents CONTENTS 3 PREFACE 6 SAMME
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7.2.4 Test systems 85 7.2.5 In vitr
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Sammenfatning og konklusioner Indle
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er ingen viden om, hvorledes den ko
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estemt biologisk respons (ED10, ED2
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vivo. The COMET-assay in vivo and g
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and antagonistic effects may be see
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1 Introduction Prepared by John Chr
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Table 1.3.1: Classification of comb
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Physicochemical interactions will t
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US EPA (1986) applied the concept o
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2.4 Test strategies to assess combi
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Figure 2.4.3.1. Isobologram of two
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CI = d1 /D1 = 1 In this case the is
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2.5 Toxicological test methods When
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3 General concepts in the risk asse
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NOAEL, this indicates that the subs
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of uncertainty i.e. differences in
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describe toxicities that appears to
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should be estimated for all endpoin
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1,2,3,6,7,8-HxCDF 0.1 1,2,3,7,8,9-H
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shows the pronounced influence of t
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Table 4.3.1 Estimates of carcinogen
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Figure 4.4.1.1. Scheme for safety e
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obvious ranking of individual const
Page 53 and 54: 4.5 Approach for assessment of join
Page 55 and 56: 4.6 Approaches currently used by re
Page 57 and 58: no internationally accepted procedu
Page 59: Figure 4.6.3.1 Flow chart of the ri
Page 62 and 63: octyltin dichloride). A number of a
Page 64 and 65: stannous chloride and cadmium chlor
Page 66 and 67: seen in the animals from the 1000x
Page 68 and 69: c TCTFP = 1,1,2-trichloro-3,3,3-tri
Page 70 and 71: 6 Interactions in toxicokinetics Pr
Page 72 and 73: once more exposed and the kinetics
Page 74 and 75: Dermis The dermis consists of a sup
Page 76 and 77: 7.1.3 Ocular irritancy 7.1.3.1 Comp
Page 78 and 79: Another in vitro test for ocular ir
Page 80 and 81: lipid peroxidation was observed, wh
Page 82 and 83: mixture. These interactions may dev
Page 84 and 85: 0.6% of live births in humans. In s
Page 86 and 87: DNA, and that the cell was capable
Page 88 and 89: (Sorsa et al. 1994, Myslak & Kosmid
Page 90 and 91: Four inhibitors of DNA topoisomeras
Page 92 and 93: cyclophosphamide-metabolising enzym
Page 94 and 95: Nickel compounds are carcinogenic t
Page 96 and 97: 7.2.8 Conclusion As shown in this r
Page 98 and 99: Since no compounds are known to cau
Page 100 and 101: In a more mechanistic sense, promot
Page 102 and 103: Several inhibitors of tumour promot
Page 106 and 107: analysis was used to predict the hi
Page 108 and 109: interaction of TCDD and retinoic ac
Page 110 and 111: and now includes compounds as diver
Page 112 and 113: Furthermore, the estrogenic effects
Page 114 and 115: Dose of A (arbitrary units) 10 8 6
Page 116 and 117: chance or experimental error. One w
Page 118 and 119: 7.6.2.3 Receptors A receptor is a b
Page 120 and 121: 7.6.5.2 Kindling Kindling is the ph
Page 122 and 123: Science Institute (RSI) have conven
Page 124 and 125: eaction with sulfhydryl groups). Th
Page 126 and 127: 7.7.1.3 Mechanisms of immunotoxicit
Page 128 and 129: tested separately. This is a phenom
Page 130 and 131: In practical life an allergen may b
Page 132 and 133: 8.3 Conference proceedings Proceedi
Page 134 and 135: with combinations of environmental
Page 136 and 137: Boyd MR, Statham CM and Longo NS (1
Page 138 and 139: De Wall EJ, Schuurman HJ and Van Lo
Page 140 and 141: theoretical considerations and a su
Page 142 and 143: Groten JP, Sinkeldam EJ, Muys T, Lu
Page 144 and 145: Howes D, Guy R, Hadgraft J, Heyling
Page 146 and 147: cytochrome P450 1A2 expressed in Am
Page 148 and 149: Lison D, Carbonnelle P, Mollo L, La
Page 150 and 151: Narotsky MG, Weller EA, Chinchilli
Page 152 and 153: Ramsey JC and Andersen ME (1984). A
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Silva E, Rajapakse N and Kortenkamp
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Leeuwen FXR, Liem AKD, Nolt C, Pete
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Wlodarczyk B, Biernacki B, Minta M,
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Combined Actions and Interactions of Chemicals in Mixtures

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