Combined Actions and Interactions of Chemicals in Mixtures

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• Hazard identification. In this step, the toxic effects (hazards) of the chemical are identified, based on reviews of the scientific literature and other information. • Hazard characterisation. For compounds for which a threshold for toxicity is assumed to exist, a no-observed-adverse-effect level (NOAEL) is derived from the most sensitive effect in the most sensitive species (if relevant for humans) or if this is not possible a lowest-observed-adverse-effect level (LOAEL). The NOAEL is the highest concentration or amount of the substance found by experiment or observation that causes no detectable adverse alterations of morphology, functional capacity, growth, development, or life span of the target organism under defined conditions of exposure (IPCS 1987). In most risk assessments the NOAEL is divided by an assessment factor (safety factor, uncertainty factor, adjustment factor, conversion factor, etc.) in order to derive an Acceptable Daily Intake (ADI), Tolerable Daily intake (TDI), Human Limit Value (HLV), Reference Dose (RfD), Acute Reference Dose (ARfD) or others. • New approaches are emerging which by use of statistical and probabilistic techniques try to determine the “true” no-adverse-effect level (NAELtrue) instead of directly using the NOAEL, which is an imprecise estimate. One such alternative is the Benchmark Dose approach, which has the advantage of using all available (and relevant) dose response data. The Benchmark Dose concept can be extended to obtain an uncertainty distribution of the Critical Effect Dose (CED) using a probabilistic approach. In addition, it has also been suggested to use a probabilistic approach to combine the CED distribution with the estimated uncertainty distributions for assessment factors in order to derive HLV, ADI, TDI, etc. as a distribution in stead of a point estimate. For a discussion of these new concepts see Vermeire et al. (1999). One major problem in using these new approaches is that they require more data on dose response relationships, than are normally produced in standard toxicological investigations. • For compounds where a threshold for the effect cannot be assumed, such as genotoxic carcinogens, most risk assessments would use probabilistic estimates of the risk. The use of probabilistic models, such as the linearized multistage model, assumes cancer as a non-threshold effect. The US EPA uses a descriptor that addresses upper bound risk, the Risk Specific Dose (RsD). In establishing a RsD for cancer it is attempted to describe the lowest possible dose, which could be interpreted to result in a specific risk e.g. one in one million. Or, as it is more commonly stated, the upper bound risk that the RsD could be projected to cause. The actual dose needed to generate a one in one million risk, for instance, could be much higher; conversely, the actual risk from the RsD could be much lower and, in fact, could even be zero. The use of the one in one million probability of cancer is an arbitrary convention which, when used consistently across chemicals, allows for the comparison of relative cancer potency. • Exposure assessment. This assessment should take into account all foreseeable exposures by relevant routes (oral, dermal, inhalation). It should also relate to exposure pattern and different populations groups (e.g. workeers, consumers, man and the environment) potentially exposed that may differ in their sensitivity to the compound/effects in question. • Risk characterisation. In this step the exposure is compared to the ADI, TDI, RfD, ARfD etc. If the exposure is less than ex. the ADI, it is by definition assumed that there is no appreciable risk. However, according to the EU Technical Guidance Documents the human risk to industrial chemicals is characterized by comparing the estimated or measured human exposure (air, water, skin, diet, inhalation, dermal, oral) to the results of the effect assessment, i.e. a NOAEL. If If the exposure estimate is higher or equal to 34
NOAEL, this indicates that the substance is of “concern” with regard to the exposed population. Where the exposure estimate is less than the NOAEL, the risk assessor should determine whether the magnitude by which the NOAEL exceeds the estimated exposure (i.g. the “margin of safety”) is of concern. This evaluation requires expert judgement to weigh the parameters of relevance for the margin of safety (e.g. intra-/interspecies variation, nature and severity of the effect, dose/response relationship, differences in exposure (route, duration, frequency and pattern)). In practise, lower “margin of safety” are normally seen for workers compared to those for consumers or humans indirectly exposed via the environment. In order to describe to use of uncertainty factors (safety factors) the principles behind the derivation and use of the ADI are outlined as an example. 3.3 The Acceptable Daily Intake (ADI) Food additives, veterinary residues and pesticide residues in foods are regulated on the basis of the Acceptable Daily Intake (ADI). The regulation should ensure that the amounts of a given chemical permitted in various foods would not result in that the consumer has a higher daily intake than the ADI. The ADI concept was originally developed in JECFA and defined as "an estimate of the amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk" (IPCS 1987). The ADI is derived from studies in humans, experimental animals and in vitro. Studies of acute, sub-acute (28-90 days) and chronic toxicity, carcinogenicity, reproductive toxicity/teratogenicity are mandatory as well as studies on metabolism and kinetics and short-term in vitro studies of mutagenicity/clastogenicity. Special studies on mechanism of actions are normally also being required. The “no observed (adverse) effect level” (NO(A)EL) is determined from the most sensitive study in the most sensitive species tested. The ADI is established from the NOEL by dividing it with a safety (uncertainty) factor (Figure 3.1.1). When the database is considered adequate a factor of 100 is used by default, but may be modified when adequate human data are available. When the database is not optimal, but there are no indications of any health problems from anticipated use, a temporary ADI may be established using a larger safety factor (200 by default, but factors >1000 have been used). 35
Page 1 and 2: Combined Actions and Interactions o
Page 3 and 4: Contents CONTENTS 3 PREFACE 6 SAMME
Page 5 and 6: 7.2.4 Test systems 85 7.2.5 In vitr
Page 7 and 8: Sammenfatning og konklusioner Indle
Page 9 and 10: er ingen viden om, hvorledes den ko
Page 11 and 12: estemt biologisk respons (ED10, ED2
Page 13 and 14: vivo. The COMET-assay in vivo and g
Page 15 and 16: and antagonistic effects may be see
Page 17 and 18: 1 Introduction Prepared by John Chr
Page 19 and 20: Table 1.3.1: Classification of comb
Page 21 and 22: Physicochemical interactions will t
Page 23 and 24: US EPA (1986) applied the concept o
Page 25 and 26: 2.4 Test strategies to assess combi
Page 27 and 28: Figure 2.4.3.1. Isobologram of two
Page 29 and 30: CI = d1 /D1 = 1 In this case the is
Page 31 and 32: 2.5 Toxicological test methods When
Page 33: 3 General concepts in the risk asse
Page 37 and 38: of uncertainty i.e. differences in
Page 39 and 40: describe toxicities that appears to
Page 41 and 42: should be estimated for all endpoin
Page 43 and 44: 1,2,3,6,7,8-HxCDF 0.1 1,2,3,7,8,9-H
Page 45 and 46: shows the pronounced influence of t
Page 47 and 48: Table 4.3.1 Estimates of carcinogen
Page 49 and 50: Figure 4.4.1.1. Scheme for safety e
Page 51 and 52: 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
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DNA, and that the cell was capable
Page 88 and 89:
(Sorsa et al. 1994, Myslak & Kosmid
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Four inhibitors of DNA topoisomeras
Page 92 and 93:
cyclophosphamide-metabolising enzym
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Nickel compounds are carcinogenic t
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7.2.8 Conclusion As shown in this r
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Since no compounds are known to cau
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In a more mechanistic sense, promot
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Several inhibitors of tumour promot
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Table 7.4.1.1 Overview of in vivo t
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analysis was used to predict the hi
Page 108 and 109:
interaction of TCDD and retinoic ac
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and now includes compounds as diver
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Furthermore, the estrogenic effects
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Dose of A (arbitrary units) 10 8 6
Page 116 and 117:
chance or experimental error. One w
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7.6.2.3 Receptors A receptor is a b
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7.6.5.2 Kindling Kindling is the ph
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Science Institute (RSI) have conven
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eaction with sulfhydryl groups). Th
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7.7.1.3 Mechanisms of immunotoxicit
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tested separately. This is a phenom
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In practical life an allergen may b
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8.3 Conference proceedings Proceedi
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with combinations of environmental
Page 136 and 137:
Boyd MR, Statham CM and Longo NS (1
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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
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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
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Narotsky MG, Weller EA, Chinchilli
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Ramsey JC and Andersen ME (1984). A
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Silva E, Rajapakse N and Kortenkamp
Page 156 and 157:
Leeuwen FXR, Liem AKD, Nolt C, Pete
Page 158:
Wlodarczyk B, Biernacki B, Minta M,
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