The world of chemicals

Transcription

1 Integration of Data for Risk Assessment: The RISK21 Philosophy and Methodology in Data Integration for Risk Assessment Timothy Pastoor, PhD, DABT, ATS 1

2 The world of chemicals Drugs Cosmetics Agrochemicals Household products Food ingredients Industrial emissions Effluent Natural toxins 2

3 RISK/SAFETY (HAZARD, EXPOSURE) HAZARD (ADVERSE EFFECT) EXPOSURE (DOSE) 3

4 The Stimuli for Change 4

5 RISK21 v1.0: By the Numbers 5

6 RISK21 Publications All OPEN ACCESS links at 6

7 How is RISK21 Different? Current Paradigm Data Generation (requirements, e.g., 40CFR, OECD, etc.) Problem Formulation Development of Conceptual Model New Paradigm Problem Formulation Development of Conceptual Model Targeted data generation based on Problem Formulation / conceptual model Selection & application of relevant data Exposure & toxicity Application of relevant data Exposure & toxicity Risk Evaluation Risk Evaluation 7

8 RISK21 Principles Problem-formulation based Exposure driven Prior knowledge Enough precision to make the decision A framework that is Flexible Transparent Visual Facilitates fit for purpose 8

9 Mode of Action Risk? Safety? In vivo 4 3 Toxicity? In vitro QSAR/ TTC Toxicity range Biomonitoring Exposure range Probabilistic Deterministic Minimal Info 2 Exposure? 1 Problem Formulation Conclude 9

10 Use of RISK21 Matrix Estimate of Human Toxicity (mg/kg) Low Mod High A F B C D E Low Mod High Estimate of Human Exposure (mg/kg) 10

11 Use of RISK21 Matrix 11

12 Probability Distributions on the RISK21 Matrix Estimate of Human Toxicity (mg/kg) Low Mod High Low Mod High Estimate of Human Exposure (mg/kg) 12

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14 Web-based tool 14

15 WEB-Based Tool Tox Tox Tox C E B S Lower Value Upper Estimate of Human Toxicity (mg/kg) Low Mod High Low Mod Estimate of Human Exposure (mg/kg) High Verdonck-RCR Exp Exp Exp Lower Value Upper 15

16 The world of chemicals Drugs Cosmetics Agrochemicals Household products Food ingredients Industrial emissions Effluent Natural toxins 16

17 RISK21 Case Studies 1. Pseudomethrin Chemicals in Drinking Water ILSI Health and Environmental Sciences Institute

18 Mode of Action Risk? Safety? 3 Toxicity? In vivo In vitro QSAR/ TTC 4 Biomonitoring Probabilistic Deterministic Minimal Info 2 Exposure? 1 Problem Formulation Conclude

19 Case Study to Test the Approach: Pseudomethrin Problem Formulation Can Pseudomethrin be used on bed nets to protect against mosquito bites? 10 th pyrethroid Determine reasonable certainty of no harm for sleeping under the treated nets Use no more than 50 animals 19

20 Tier 0 Exposure Phys/Chem: Low volatility; therefore, inhalation negligible. Sub-chronic to chronic duration Use Age Dermal contact (mg/kg/d) Hand to mouth (mg/kg/d) Net mouthing (mg/kg/d) Total / aggregate (mg/kg/d) Net dipping (single exposure) Adult N/A N/A Child N/A N/A Infant N/A N/A N/A N/A Sleeping under net (chronic exposure) Adult N/A N/A Child e N/A Infant e WHO (2004): A generic risk assessment model for insecticide treatment and subsequent use of mosquito nets 20

21 Pyrethroid Neurotoxicity Administration to test animals and insects has identified two distinct poisoning syndromes: Type I: Aggressive sparring, increased sensitivity to external stimuli, fine tremors progressing to whole body tremors Type II: Pawing and burrowing, profuse salivation, course tremors progressing to seizures Mixed: some pyrethroids cause signs of both syndromes Effects correlate with structure: 21

22 Toxicity Values for Pyrethroids Type I non-cyano Type II alpha-cyano Shortterm/ Acute BMD20 (Single Dose) Permethrin Bifenthrin Resmethrin S-Bioallethrin Cyfluthrin Cypermethrin Pseudomethrin Esfenvalerate Fenpropathrin lambda- Cyhalothrin Intermed. Ref 90d NOEL Long- Term/ Ref Chron Chronic NOEL Highest and lowest values for each row are bolded 22

23 Sleeping under net: Tier 0 10x UF 100x UF Exposure range: mg/kg/d (infant, aggregate, sleeping) Toxicity value: most potent chronic NOAEL (lambda-cyhalothrin): UFs 23

24 Common Mechanism of Toxicity Target Tissue Dose Voltage Gated Sodium Channel Alterations Altered Neuronal Excitability In Vivo Clinical Signs All Pyrethoids modify the kinetics of VGSC activation and inactivation in mammalian neurons Changes in VGSC kinetics produce alterations in neuronal excitability. Changes in neuronal excitability underlie the clinical signs of pyrethroid toxicity 24

25 Toxicity Values for Pyrethroids Type I non-cyano Type II alpha-cyano Permethrin Bifenthrin Resmethrin S-Bioallethrin Cyfluthrin Cypermethrin Pseudomethrin Esfenvalerate Fenpropathrin lambda- Cyhalothrin BMD Ref 90d NOEL Ref Chron NOEL MEA IC fold difference in potency between pseudomethrin and most-potent 25

26 Sleeping under net: 2 nd Assessment 100x UF Exposure range: (infant, aggregate, sleeping) dermal absorption estimates Toxicity range: [derived from most potent chronic NOAEL (lambda-cyhalothrin) and 5-fold lower potency of pseudomethrin based on MEA IC50] + UFs 26

27 Sleeping under net: 3 rd Assessment 100x UF Exposure range: same as previous Toxicity range: Used 5-day dog study (neurological NOAEL of 1 mg/kg/d) with UF and in vitro screens 27

28 Is this what Tox21 is asking? Full Regulatory Studies Package Risk 21 Stepwise Assessment Primary Effect Neurotoxicity Neurotoxicity Other Effects None significant; from full package None significant; from ToxCast assays Short term relevant NOEL 1mg/kg from dog study 1mg/kg from dog study Long term relevant NOEL 1mg/kg from dog study 1mg/kg from dog study Number of animals used

29 RISK21 Case Studies 1. Pseudomethrin Chemicals in Drinking Water ILSI Health and Environmental Sciences Institute

30 Case Study to Test the Approach: Water Problem Formulation A regulatory agency has identified 20 chemicals that have been detected in surface and ground water that could potentially appear in drinking water. You have ONE year to decide whether risk management is required for any or all chemicals as potential drinking water contaminants. Maximize use of existing knowledge 30

31 Water Case Study: General Approach Tier 0: Utilize solubility as a worstcase exposure estimate and compare to TTC Tier 1: Utilize Tier 1 exposure model estimates and compare to TTC Tier 2: Utilize Tier 1 exposure model estimates and compare to existing chronic toxicity values 31

32 20 Selected Chemicals: Tier 0 Information CHEMICAL Water Solubility (mg/l) Exposure value (based on solubility) (mg/kg bw/d) Cramer Class TTC (mg/kg/d) Styrene Chlorobenzene ,4-Dioxane Hexachlorobenzene E Methyl tert-butyl ether Toluene diisocyanate SA ,2-Dibromo-3-chloropropane (DBCP) SA Heptachlor epoxide SA Picloram Oxyfluorfen SA Dimethipin Chlordane Fenarimol Fenoxycarb OP/Carbam Fenoxaprop-P-ethyl alpha-hexachlorocyclohexane Toxaphene E ,4,5-TP (Silvex) Quizalofop-P-ethyl Fomesafen sodium SA

33 TTC Values and the RISK21 Matrix 33

34 Exposure refinement of 18 remaining chemicals CHEMICAL Water Solubility (mg/l) Exposure value (based on solubility) (mg/kg bw/d) Refined Exposure value (mg/kg bw/d) Styrene E-5 Chlorobenzene E-3 1,4-Dioxane E-5 Methyl tert-butyl ether Toluene diisocyanate ,2-Dibromo-3- chloropropane (DBCP) E-4 Heptachlor epoxide E-3 Picloram E-3 Oxyfluorfen E-4 Dimethipin E-4 Chlordane E-4 Fenarimol E-3 Fenoxycarb E-6 Fenoxaprop-P-ethyl E-06 alpha- Hexachlorocyclohexane E-6 2,4,5-TP (Silvex) E-6 Quizalofop-P-ethyl E-05 Fomesafen sodium E-04 34

35 Exposure refinement of 18 remaining chemicals 35

36 Tier 2: Toxicity Refinement for 9 chemicals CHEMICAL Refined exposure estimate (mg/kg bw/d) Available toxicity value Toxicity data source Chlorobenzene 3E-3 NOAEL = 19 mg/kg/d Methyl tert-butyl ether NOAEL= 300 mg/kg/d Toluene diisocyanate 0.8 LOAEL = 30 mg/kg/d 1,2-Dibromo-3- Oral MRL = chloropropane 7E-4 mg/kg/d wq/1,2-dibromo-3-chloropropane.pdf (DBCP) Heptachlor epoxide Picloram 1E-3 LOAEL = mg/kg/d 2.9E-7 5.4E-03 NOEL = 7 mg/kg/d Oxyfluorfen 2.4E-4 LOAEL = 33 mg/kg/d Fenarimol 2.2E-3 NOAEL = 0.6 mg/kg/d Fomasafen sodium 3E-4 NOAEL = 0.25 mg/kg/d c3.pdf n_red.pdf D=EPA-HQ-OPP ;oldLink=false hbp/r pdf 36

37 Tier 2: Toxicity Refinement for 9 chemicals 37

38 Water Case Study Overview of Results 38

39 Mode of Action Risk? Safety? 3 Toxicity? In vivo In vitro QSAR/ TTC 4 Biomonitoring Probabilistic Deterministic Minimal Info 2 Exposure? 1 Problem Formulation Conclude

40 For more information: Visit Contact: Michelle Embry 40