Challenges of MoA/HRF under CLH

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1 Challenges of MoA/HRF under CLH Marja Pronk (RAC member) MoA/HRF Workshop, 4 November 2014

2 CLP Regulation on MoA Part 1. General principles for C&L Expert judgement & weight of evidence determination The quality and consistency of the data shall be given appropriate weight. Information on [ ] shall be considered as appropriate, as well as site of action and mechanism or mode of action study results. ( ) For the purpose of classification for health hazards (Part 3) route of exposure, mechanistic information and metabolism studies are pertinent to determining the relevance of an effect in humans. When such information [ ] raises doubt about relevance in humans, a lower classification may be warranted. When there is scientific evidence that the mechanism or mode of action is not relevant to humans, the substance or mixture should not be classified. ( ) 2

3 CLP Regulation on MoA Part 3. Health hazards 3.6 Carcinogenicity For the purpose of classification for carcinogenicity, substances are allocated to one of two categories based on strength of evidence and additional considerations (weight of evidence). ( ) Generally there is a requirement for more complete information to decrease than to increase the level of concern. ( ) Some important factors which may be taken into consideration, when assessing the overall level of concern are: [ ] (k) mode of action and its relevance for humans, such as cytotoxicity with growth stimulation, mitogenesis, immunosuppression, mutagenicity. ( ) 3

4 CLP Regulation on MoA Part 3. Health hazards 3.7 Reproductive toxicity For the purpose of classification for reproductive toxicity, substances are allocated to one of two categories. Within each category, effects on sexual function and fertility, and on development, are considered separately. In addition, effects on lactation are allocated to a separate hazard category. ( ) Classification is made on the basis of the appropriate criteria [ ] and an assessment of the total weight of evidence [ ] Substances shall not be so classified [as reproductive toxicant] if such an effect is produced solely as a nonspecific secondary consequence of other toxic effects. ( ) 4

5 CLP Regulation on MoA Part 3. Health hazards 3.7 Reproductive toxicity (cont d) Toxicokinetic studies in animals and humans, site of action and mechanism or mode of action study results may provide relevant information which reduces or increases concerns about the hazard to human health. ( ) If it is conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a substance which produces an adverse effect on reproduction in experimental animals should not be classified. ( / ) 5

6 CLP hazard categories Category 1A Category 1B Category 2 Carcinogenicity Known to have carcinogenic potential for humans Largely based on sufficient human evidence Presumed to have carcinogenic potential for humans Largely based on sufficient animal evidence (sometimes on combination of limited human and limited animal evidence) Suspected human carcinogen Evidence (from limited human data or limited animal data) not sufficiently convincing for 1A/1B Reproductive toxicity Known human reproductive toxicant Largely based on human evidence Presumed human reproductive toxicant Largely based on clear animal evidence. When mechanistic info raises doubt on human relevance, cat.2 may be more appropriate. Suspected human reproductive toxicant Some evidence (from humans or animals), not sufficiently convincing for 1A/1B 6

7 3.6 Carcinogenicity CLP Guidance on MoA Classification of a substance as a carcinogen requires expert judgement and consideration of many different factors (weight and strength of evidence) Strength of evidence: enumeration of tumours and their level of statistical significance Weight of evidence: additional factors to be considered, either increasing or decreasing the level of concern for human carcinogenicity (and thus classification category) Generally there is a requirement for more complete information to decrease than to increase the level of concern Guidance does not provide hard and fast rules, but suggests a stepwise approach to classification where all factors that may influence the outcome are considered systematically (reference to a.o. WHO/IPCS MoA/HRF, without further details) 7

8 CLP Guidance on MoA 3.6 Carcinogenicity (cont d) Some important factors to consider (increasing or decreasing the level of concern): (a) tumour type and background incidence (b) multi-site responses (multiple sites and/or multiple species) (c) benign or malignant tumours; progression to malignancy (d) reduced tumour latency (e) whether responses are in single or both sexes (f) whether responses are in a single or several species (g) structural similarity to carcinogenic substance(s) (h) routes of exposure (standard vs non-physiological) (i) comparison of toxicokinetics between test animals and humans (j) possibility of a confounding effect of excessive toxicity at test doses (MTD, ±10% reduction in body weight gain) (k) mode of action and its relevance for humans 8

9 3.6 Carcinogenicity (cont d) CLP Guidance on MoA Ad (a) tumour type and background incidence Some tumour types in animals of less/no relevance to humans: tumours occurring in tissues with no human equivalent (examples given in guidance: forestomach, Zymbal s gland, Harderian gland) tumours arising in a tissue known to be overly susceptible to tumour development in the species/strain tested (guidance presents examples of animal strains/tissues with a high spontaneous tumour incidence) tumours arising via a mode of action which does not occur in humans (see (k)) Historical control data (HCD) may provide additional info: on aberrant concurrent control incidences on relevance of low-incidence findings (e.g. rare tumours) on relevance of marginal increases in tumour incidences, especially for tumours with high background incidences 9

10 3.6 Carcinogenicity (cont d) CLP Guidance on MoA Ad (k) mode of action and its relevance for humans Only if MoA of tumour development is conclusively determined not to be operative in humans may the carcinogenic evidence for that tumour be discounted [for classification]. The existence of a secondary mechanism of action with the implication of a practical threshold above a certain dose level [ ] may lead to a downgrading of Cat.1 to Cat.2 classification. To establish a MoA will usually require specific investigative studies over and above the standard carcinogenicity study. MoA in and of itself, or consideration of comparative metabolism, should be evaluated on a case-by-case basis and are part of an analytic evaluative approach to be able to conclude with confidence that tumours are being induced through that specific mechanism to determine the relevance of the results to humans. Example of such an approach: WHO/IPCS MoA/HRF 10

11 CLP Guidance on MoA Some mechanisms of tumour formation considered not relevant for humans Type of MoA Kidney tumours in male rats associated with α2u-globulin nephropathy Pheochromocytomas in male rats secondary to hypoxemia Leydig cell adenomas induced by dopamine anta-gonists or gonadotropin-releasing hormone (GnRH) IARC, 1999 Source Ozaki et al., 2002 EU Spec. Exp., 2004 RIVM, 2004 Urinary bladder tumours due to crystals IARC, 1999 Forestomach tumours in rodents following gavage administration of irritating or corrosive, non-genotoxic substances Certain thyroid tumours in rodents mediated by UDP glucuronyltransferase (UDPGT) induction Liver tumours in rodents linked to peroxisome proliferation RIVM, 2003 IARC, 2003 EU Spec. Exp., 1999 IARC, 1999 IARC,

12 CLP Guidance on MoA 3.7 Reproductive toxicity Considerations relevant to classification Although included in the criteria, the guidance does not specifically deal with toxicokinetic differences between animals and humans, or with mode of action and relevance to humans Also no guidance on how (use of) HCD, structurally similar reproductive toxic substance(s), responses in single or both sexes or in single or more generations etc. can decrease/increase level of concern for human reproductive toxicity (and thus classification category) Only consideration addressed: presence of parental toxicity (marked systemic effects, specific parental effects) 12

13 Some RAC experiences with CLH dossiers HCD used to downgrade/discount findings BUT not always provided, or information necessary to assess their quality not provided Only for relatively few substances non-relevance of particular developmental effect to humans claimed, whereas for tumours this is more often the case BUT when claimed, fairly limited information provided to support proposed MoA and to exclude other possible MoAs (MoA/HRF not used often) Presence of maternal toxicity often used as argument for no classification BUT usually little evidence presented that effect on offspring is (non-specific) secondary consequence (rather than direct effect) More guidance needed? 13

14 Liver tumours Possible MoAs I. DNA reactivity II. Increased cell proliferation A. Receptor mediated 1. PPARα (peroxisome proliferation) in CLP guidance 2. Enzyme induction (CAR, PXR, AhR) 3. Estrogen 4. Statins 5. Cytotoxicity 6. Other B. Non-receptor mediated 1. Cytotoxicity 2. Infections 3. Iron (copper) overload 4. Increased apoptosis 5. Other (Cohen, 2010; in bold: MoA likely to be relevant to humans) 14

15 Liver tumours Some examples Sulfoxaflor Imazalil DS proposal No class. (PB-like MoA) Carc. 2 (PB-like MoA) Industry RAC assessment Not relevant Basis: non-relevance to humans shown by extensive mechanistic data and HRF Not relevant Basis: extensive data and use of HRF point to CAR/(PXR)- mediated MoA. Evidence that last event in MoA (proliferation) does not occur in humans. Alternative MoAs shown to be less likely involved. Not relevant Basis: non-relevance to humans shown by extensive mechanistic data Relevant Carc. 2 Basis: data (brief summaries only) point to similarities with PB as to CAR/(PXR)-activation as most plausible MoA. But human irrelevance not sufficiently shown (data on proliferation in humans equivocal). 15

16 Thyroid follicular tumours Possible MoAs compound has genotoxic properties compound is non-genotoxic Carc. 1B or 2 e.g. via UDPGT induction in CLP guidance possible disturbance of thyroid-pituitary axis clearly established mechanism, by, for example enhancement of TH metabolism inhibition of TPO inhibition of 5 -monoiodinase inhibition of iodine uptake inhibition of TH release TSH receptor agonist mechanism unknown; insufficient data Carc. 2 low potency medium potency high potency no classification (Spec. Exp., 1999) 16

17 Thyroid follicular tumours Some examples Etofenprox Imazalil Iodomethane DS proposal Industry RAC assessment No class. Not relevant Not relevant Benign tumours, some MoA info that effect is likely to be secondary to hepatic microsomal enzyme induction (UDPGT; reference to CLP guidance, Spec.Exp.), low potency, not genotoxic Removal of Carc.2 Not relevant Relevant keep Carc. 2 MoA is perturbation of thyroid hormone homeostasis by a nongenotoxic substance (reference to Spec.Exp.). Thyroid cancer in humans is rare. No UDPGT induction seen; quant. rather than qual. species differences in perturbation; new data point to thyroid cancer rate in man, TSH as risk factor. 17

18 Developmental toxicity some examples DS proposal Repr. 1B Epoxiconazole Industry RAC Basis: 1) post-implantation loss/resorptions 2) malformations (cleft palates) 1) not relevant, 2) reasonable doubt about relevance Basis: 1) Several studies claiming effects to be secondary to ED effects in rat dams, but not relevant to humans because of differences in hormonal regulation of pregnancy/parturition (guinea pig better model; negative) 2) High dose effect, at levels causing maternal toxicity. Some MoAs suggested but not studied. No cleft palates in guinea pigs. Relevant Repr. 1B Basis: 1) MoA (aromatase inhibition) occurs also in humans; similar effects seen with other azole in primates 2) Typical class effect, also seen at non-maternally toxic doses; MoA not clear. 18

19 Developmental toxicity some examples DS proposal Industry No class. Sulfoxaflor (for neonatal deaths and foetal abnormalities in rats) Not relevant Flumioxazin Removal of Repr. 1B (for embryolethality, teratogenicity, growth retardation in rats) Not relevant RAC assessment Basis: non-relevance to humans of single MoA for both effects shown by extensive mechanistic data and HRF Not relevant Basis: extensive data and use of HRF point to single MoA that is rat-specific. Alternative MoAs shown (mostly indirectly) to be less likely involved. Basis: non-relevance to humans of single MoA for all effects shown by extensive mechanistic data and HRF Relevant keep Repr. 1B Basis: single MoA plausible, but human irrelevance not sufficiently shown (essential study missing, quantitative rather than qualitative differences). 19

20 In assessing MoA(/HRF) data Challenges for RAC Considerable amount of data required to substantiate MoA Expertise ( external experts needed?) Time constraints ( concise presentation of crucial data) No hard and fast rules ( always expert judgement involved) What and how much scientific evidence is sufficient to conclusively determine MoA ( more guidance needed: on HRF? demonstration of (all) key events? demonstration that one (or more) key events do not occur in humans? in vitro data sufficient? how valid is use of models (e.g. with KO mice)? demonstration that other possible MoAs are unlikely?) 20

21 Challenges for RAC In assessing MoA(/HRF) data cont d Can it be generalised (into factsheet, AOP, etc.) or always case-by-case? Some tumour types considered not relevant in guidance, but not clear from references provided what are key events to be shown for MoA involved ( more guidance needed) 21

22 Challenges for RAC In deciding on C&L when MoA(/HRF) data are available Unclear CLP criteria/guidance (raises doubt, conclusively determined, sufficient/clear/limited/some evidence, ) Distinction between no concern (leading to no classification) and low concern (leading to a lower classification than anticipated) Lack of definitions (mode vs. mechanism, presumed vs. suspected, no vs less/doubtful relevance, ) History of RAC decisions How to deal with other recent regulatory decisions/ assessm.? Relevance of the effect for humans: how much and what kind of data suffice? Is there any difference if humans are less sensitive to the effect or if the effect is not operative in humans? 22

23 Challenges for RAC In deciding on C&L when MoA(/HRF) data are available cont d Some MoAs are mentioned in guidance, but still up-to-date? ( regularly update, taking into account new evidence, new trends in cancer development, etc.?) Are there other non-relevant MoAs identified in the mean time that should be included in the guidance? Who decides when MoA is not relevant for humans? ( expert consultation, international consensus, valid for all regulatory frameworks) Is there a difference from risk or hazard assessment point of view? 23

24 PLENTY OF CHALLENGES! THANK YOU FOR YOUR ATTENTION

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