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Health Risk Assessment Mark Martens and Dominique Lison

Health Risk Assessment Mark Martens and Dominique Lison. Beltox Seminar, Part 5.3. Dose-effect Relationship (1). Progression of effects with dose. Necrotic liver cells. Severity/incidence of toxic effects. Convulsions. Liver weight. Dose.

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Health Risk Assessment Mark Martens and Dominique Lison

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  1. Health Risk AssessmentMark Martens and Dominique Lison Beltox Seminar, Part 5.3

  2. Dose-effect Relationship (1) Progression of effects with dose Necrotic liver cells Severity/incidence of toxic effects Convulsions Liver weight Dose In one toxicology study several pathologic endpoints can be identified with each of them emerging at different dose levels and having a different dose-effect relationship

  3. Determinants of Hazard that can be derived from Toxicity Testing • NOEL: No Observed Effect Level • NOAEL: No Observed Adverse Effect Level • LOEL: Lowest Observed Effect Level • LOAEL: Lowest Observed Adverse Effect Level • MTD: Maximum tolerated dose

  4. Dose-effect Relationship (2) Threshold approach Severity/incidence of toxic effects (difference from control) Liver weight Threshold of concern (ToC) for liver wt Dose NOEL NOAEL LOEL MTD Each pathology has its own threshold of concern : Toxic effect at each dose used in the experimental design

  5. Dose-effect Relationship (3) Integrated threshold approach Severity/incidence of toxic effects (difference from control) Necrotic liver cells Convulsions Liver weight ToC liver wt ToC liver necrosis ToC convulsions Dose NOEL NOAEL LOEL MTD Most used method for the derivation of a safe dose in risk assessment : Toxic effect at each dose used in the experimental design

  6. Dose-response Relationship (4) Benchmark approach Incidence (%) of a defined toxic effect (e.g. tumour bearing animals) 5% Dose ED0.001 ED1 ED5 Only used when sufficient data points are available to permit low dose extrapolation

  7. Dose-effect Relationship (5) Most relevant and sensitive toxic effect (e.g. liver necrosis in the dog) MTD Dose LOEL NOAEL NOEL Up to 5 days 1 month 3 months 9 months The longer the time of exposure the lower the safe dose

  8. Human Safe Dose (1) NOAEL of the most sensitive and/or representative animal species Inter-species uncertainty factor Extrapolation on basis of body surface Modification factors Human equivalent of NOAEL Intra-species uncertainty factor Human safe dose/concentration

  9. Human Safe Dose/Concentration (2) • ADI: Allowable daily intake (food risk assessment) • RfD: Reference dose (food risk assessment) • FIH start dose: Lowest dose to start single administration of an experimental drug for the first time in man (drug risk assessment) • TLV: Threshold limit value (occupational risk assessment) • OEL: Occupational exposure limit (occupational risk assessment)

  10. Uncertainty Factors (UF) • Inter-species extrapolation (UF = 1, 2, 3, 6, 12) • LOEL to NOEL/NOAEL extrapolation (UF= 1,3,10) • Sub-chronic to chronic extrapolation (UF = 1,3,10) • Route to route extrapolation (UF = 0.01 to 100) • Inter-individual variability in human population (UF = 1,3,10)

  11. Modification Factors (MF) • Too small number of animals in critical studies (MF>1) • Results are poorly described (MF>1) • Important studies were not conducted (MF>1) • Results are borrowed from similar molecules (MF>1) • Severe effects (MF>1) • Irreversible effects (MF>1)

  12. Risk Characterisation Exposure assessment Hazard identification Dose-effect relationship Risk characterisation Risk management

  13. Safety Margin Human safe dose/concentration Safety margin = Highest possible exposure The safety margin is a measure for risk, the greater the safety margin the less likely it is that an adverse health effect will occur over a defined period of time

  14. Risk Assessment (1) Pesticide residues in food • Question: • Should food treated with a pesticide be safe for human consumption for a life-time? • Answer: • Yes • Any health effect related to the exposure to that pesticide will not be tolerated

  15. Risk Assessment (2) • Specific characteristics of food risk assessment: • It should be technically feasible to attain the safe pesticide concentration in the crop/food (waiting time and spraying dose are important factors) • The allowable daily intake (ADI) should not be exceeded taking dietary composition of a given population into account • Foods should be regularly checked for pesticide residues to make sure that the limit concentrations are not exceeded • Pesticides are subject to a regulatory process where the residue limits must be proposed and justified on the basis of toxicology studies and best agricultural practices

  16. Risk Assessment (3) Human safe Dose (oral intake of pesticides) NOEL/NOAEL x BW ADI = UF1-5 x MF1-6 ADI: Allowable daily intake (over life-time) BW: Body weight (50 to 70 kg) UF: Uncertainty factors (up to 5) MF: Modification factors (up to 6)

  17. Risk Assessment (4) Occupational chemicals • Question: • Should a worker be exposed to chemicals in the workplace without any adverse health effects? • Answer: • Yes, but • If the exposure to the chemical in the atmosphere or onto surfaces cannot be reduced below the OEL then appropriate protective equipment should be worn.

  18. Risk Assessment (5) • Specific characteristics of occupational risk assessment: • The exposure limits should be technically achievable (exhaust ventilation systems, cleaning procedures) • The systemic (whole body) daily exposure attained via inhalation or via the skin should not be exceeded taking the frequency and duration of exposure into consideration • Inhalation toxicology studies are complicated and very expensive and thus rarely available. Therefore, in most cases, the inhalation and skin exposure limits are derived from oral toxicology studies and epidemiology (when people are already exposed) • Protective equipment (gloves, masks, respiratory apparatus, boots, garments) should be checked regularly to ensure that the body burden is not exceeded • Workers being exposed regularly to chemicals (even when exposures remain below the OEL or when protective equipment is worn) should be checked regularly by the occupational physician and followed by atmospheric and biological monitoring

  19. Risk Assessment (6) Human safe Concentration (inhalation of chemicals) ADI x Fabs OEL = V8h OEL: Occupational exposure level ADI: Allowable daily intake (over life-time) via the oral route Fabs: Fraction absorbed via the oral route V8h: Volume inhaled in a 8 hour working day (10 m3) Assumption: Complete absorption via the inhalation route

  20. Risk Assessment (7) Drugs • Question: • Should a drug be taken for the duration of the therapy without any side effects? • Answer: • Yes, but • Side effects are accepted in function of the life-saving potential of the drug (e.g. some toxicity is allowed in the case of cancer drugs whereas no side effects,or only very few, are allowed for comfort drugs)

  21. Risk Assessment (8) • Specific characteristics of drug risk assessment: • The maximum daily dose for a given therapeutic period (several days to life-time) should not produce any unacceptable side effects based on safety data generated in a large number of patients (phase III trials) for the time or a significant proportion of the projected treatment time • Any possible adverse effects that are unacceptable to man should be identified (e.g. irreversible effects, allergies, mutagenicity) • Health effects that cannot be demonstrated in clinical studies such as birth malformations and cancer should be assessed by specific toxicology studies • Human volunteers receiving an experimental drug for the first time are extensively monitored (clinical signs, ECG, hematology, serum chemistry, specific tests selected on the basis of toxicology studies and pharmacokinetics)

  22. Risk Assessment (9) Human safe Dose (1st dose in man for drugs) NOEL/NOAEL x BW x scaling factor Start dose for FIH = UF FIH: First in human single dose trial BW: 60 to 70 kg UF: 10 Scaling factor: extrapolation to man on the basis of body surface (0.08 for mouse, 0.16 for rat, 0.54 for dog)

  23. Human safe Dose (1st dose in man for drugs)Example • The dog is selected as the most sensitive and most representative species for this drug (on the basis of toxicology,metabolism and PK data) • NOAEL in dogs is 60 mg/kg/day after 28 days of treatment • The sentinel toxicity endpoint is hepatocellular necrotic foci with increase of liver biomarkers (AST, ALT) • There are no effects on vital functions (cardiovascular, respiratory, CNS) • The drug candidate is not mutagenic 60 mg/kg/day x 70 kg x 0.54 Start dose for FIH = = 227 mg/day 10 Body surface scaling factor dog  man NOAEL Intra-species uncertainty factor Body weight of male volunteers

  24. Risk Assessment: Some Considerations • FIH start dose, ADI, OEL, ... are guidance values, based on animal experimental data, mathematical constructs and hypothetical assumptions, to assist in the management of public health (population level) • FIH start dose, ADI, OEL are not magic values delimiting safety from toxicity. They should be considered to be the best possible estimate and should be regularly reviewed on the basis of new data (toxicology, epidemiology, occupational medicine) • They are not to be considered as applicable to the level of a single individual but rather at the level of a population

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