Health Assessment - Toxicology Assessment

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On this page:

• Scientific Evaluation and Decision Making Human Health Risk Assessment for Pesticides in Canada
• Presentation Outline
• Human Health Risk Assessment Process
• Risk Assessment Paradigm
• Toxicology Assessment - Objectives Identify potential hazards to human health
• Toxicology Data Requirements
• Toxicology Data Requirements Variations
• Acute Toxicity Studies
• Acute Toxicity Studies
• Evaluation of Formulants in End-Use Products
• Metabolism/Toxicokinetics
• Subchronic Studies
• Chronic/Oncogenicity Studies
• Genotoxicity/Mutagenicity Studies
• Reproductive Toxicity
• Developmental Toxicity
• Neurotoxicity and Developmental Neurotoxicity
• Additional Studies
• Epidemiology Studies
• Reference Dose Determination
• Acute Reference Dose
• Acceptable Daily Intake
• Toxicological Endpoint Selection: Occupational and Bystander Risk Assessments
• Uncertainty Factors and PCPA Factor
• Cancer Risk
• Re-evaluation versus New Products
• Summary - Overall Hazard Assessment Multi-Step Approach
• References/Links

Scientific Evaluation and Decision Making Human Health Risk Assessment for Pesticides in Canada

Deborah Ramsingh
Senior Evaluation Officer, Antimicrobial/Insecticide Toxicology Evaluation Section
Health Effects Divison I
Health Evaluation Directorate

Presentation Outline

• Human health risk assessment process
• Objectives of the toxicology assessment
• Toxicology data requirements
• Study types
  • Critical elements
  • Common problems
• Reference dose determination
• Summary - Overall hazard assessment
• Additional Information

Human Health Risk Assessment Process

• Structured framework
• Consistent with international approaches

Risk Assessment Paradigm

Toxicology Assessment - Objectives Identify potential hazards to human health

1. Characterize inherent hazard
   • Toxicity studies - different durations, various routes, examining several different types of endpoints
2. Identify potential for effects on human health based on exposure scenarios
   • Route (dietary and non-dietary)
   • Duration
3. 3.Determine acceptable levels for human exposure

Toxicology Data Requirements

• Standardized DACO tables
  • Data requirement must be satisfied with acceptable study or a valid scientific waiver rationale
• Studies must follow GLP and be conducted according to internationally accepted guidelines (OECD Section 4, USEPA OPPTS Series 870)
• Requirements vary for different types of pesticides

Toxicology Data Requirements Variations

• Conventional pesticides (DIR2005-01)
  • Antimicrobials
• Racemic mixture/isomers - bridging data
• Microbials (DIR2001-02)
• Pheromones (PRO2002-02)
• Low-risk pesticides (PRO2007-02)
• Contaminants (NOI2005-01)
• Formulants (DIR2006-02)

Acute Toxicity Studies

• Required for active ingredients and end-use products
• Health effects that may result from a single, high dose via various routes:
  • Oral, dermal and inhalation lethal doses
  • Eye and skin irritation indices
  • Dermal sensitization potential
• Used as the basis for precautionary label statements

Acute Toxicity Studies

• Critical Elements
  • Inhalation: chamber description, equilibration time, particle size distribution (MMAD+GSD), test up to 2 mg/L limit (describe if limit cannot be achieved), corrections made to concentration (describe if applied)
  • Sensitization: ensure adequate induction, inclusion of reaction scores, results of preliminary irritation tests, proper controls
• Common Problems
  • Concentrations used in skin sensitization studies not high enough
  • Poor positive control results in skin sensitization studies
  • Inappropriate/inconsistent vehicle choices

Evaluation of Formulants in End-Use Products

• Specification Form - concentration of each formulant
  • Assess level relative to existing use pattern
• Classification as per EPA/PMRA List of Formulants
  • If new formulant, additional data may be required in order to assign classification
• MSDS, other available information (literature)

Metabolism/Toxicokinetics

Radio labelled test material

Single low dose, single high dose, repeat low dose; usually oral

Absorption

Blood/plasma kinetics

Distribution to tissues

Bioaccumulation potential, identify target organs

Metabolism

Metabolic pathway, metabolite identification, determine toxicological significance

Excretion

Urinary, fecal, bile, expired air, % recovery of administered dose

• Critical Elements:
  • Compare results between dose regimens and sexes
  • Comparison of metabolites to those identified in crops, livestock, environmental matrices
• Common Problems:
  • Lack of biliary excretion assessment when fecal excretion high

Subchronic Studies

• Effects of repeated exposures over several weeks to 1 year
• Various routes -oral, dermal, inhalation
• Various species -rat, rabbit, mouse, dog
• Critical Elements
  • Adequate dose levels, distribution of doses
  • Ensure MTD has been achieved
  • Identify all endpoints of toxicity over entire study period
  • Correlate findings
• Common Problems:
  • Usually well performed

Chronic/Oncogenicity Studies

• Long-term effects, including cancer, that may result from exposure over most of an animal's lifetime
• Rat (2 years) and mouse (18 months) - daily exposures
• Critical Elements
  • Adequate dose levels and distribution, ensure MTD reached
  • Adequate survival rates
  • Identify all endpoints of toxicity over entire study period
  • Describe tumour profiles
  • Historical control data - common and rare tumours
  • Correlate findings
• Common Problems
  • Lack of historical control data

Genotoxicity/Mutagenicity Studies

• Assess pesticide interaction with DNA that results in mutations or other damage
• Bacterial and mammalian cell systems; in vivo and in vitro assays
• Used in assessment of carcinogenic potential
• Critical Elements
  • Precipitation
  • Cytotoxicity
  • Proper controls
  • Historical control data
• Common Problems
  • Doses not high enough, not enough dose levels
  • Ames - proper combination of strains not used

Reproductive Toxicity

• Assess effects on reproduction and offspring growth
• Evaluation of potential sensitivity
• Conducted over at least 2 generations
  • Examination of transgenerational effects
• Critical study for evaluation of endocrine modulation potential
• Critical Elements
  • Dosing period
  • Dose levels during pre-mating, gestation, lactation - adequate dose levels (MTD)
  • Historical control data
• Common Problems
  • Unclear reporting of caesarean data, litter parameters

Developmental Toxicity

• Effects on the developing fetus (birth defects)
• Pregnant animals (2 species - usually rat and rabbit) are dosed during the critical stages of fetal development (major organogenesis)
• Evaluation of potential sensitivity
• Critical Elements
  • Dosing period, date of sacrifice
  • Adequate dose levels (MTD)
  • Effects reported as litter vs fetal basis
  • Historical control data
• Common Problems
  • Unclear description of rare findings
  • Unusual/inconsistent terminology

Neurotoxicity and Developmental Neurotoxicity

• Studies triggered for certain chemicals
  • e.g. insecticide with neurotoxic mode of action, signs of neurotoxicity in standard toxicity database
• Neurotoxic potential from single or repeated exposures in the adult
• Neurotoxic potential during development
  • Evaluation of potential sensitivity
• Critical Elements
  • Adequate dose levels (MTD)
  • Historical control data
  • Positive control data
• Common Problems
  • Histopathology not examined at all doses when effect at high dose
  • Inappropriate statistical analysis
  • DNT studies: high variability in controls in the assessment of behavioural endpoints (demonstration of technical competence)

Additional Studies

• Immunotoxicity
  • May be required if possible indicators of impaired immune function are evident in chronic or subchronic studies
• Mechanistic studies
• Peer-reviewed published research

Epidemiology Studies

• Published and unpublished studies
• Information considered in conjunction with ongoing re-evaluation of pesticides, and for first-time registrations when available (e.g. from other countries)
• Used in the overall weight of evidence

Reference Dose Determination

• Identify critical NOAELs for threshold effects
  • Consider route/duration in determining relevance to human exposure scenarios
• Identify uncertainty factors/PCPA factor
• Establish dietary reference doses
  • Acute Reference Dose (ARfD)
  • Acceptable Daily Intake (ADI)
• Identify toxicological endpoints and target MOE for occupational and residential exposure scenarios
• Determine cancer risk

Acute Reference Dose

• ARfD: the amount that can be ingested orally on any given day without any human health concerns

NOAEL (mg/kg bw)
Uncertainty Factor (100X minimum)

Acceptable Daily Intake

• ADI: the amount that can be ingested orally over a lifetime without any human health concerns

NOAEL (mg/kg bw/day)
Uncertainty Factor (100X minimum)

Toxicological Endpoint Selection: Occupational and Bystander Risk Assessments

• Oral, dermal and/or inhalation
• Short-term (1-30 days), intermediate-term (1-6 months), and/or long-term (>6 months)
• Incidental exposure scenario (oral, dermal) for toddlers (e.g. turf uses)

Uncertainty Factors and PCPA Factor

• Standard Uncertainty Factor (10 x 10 = 100)
  • Interspecies extrapolation (10x)
  • Intraspecies variability (10x)
• Additional Uncertainty Factors
  • Using a LOAEL instead of a NOAEL
  • Using a short-term NOAEL for a long-term exposure scenario
  • Database deficiencies
• PCPA factor
  • Potential prenatal and postnatal toxicity; completeness of data with respect to exposure of and toxicity to infants and children

Cancer Risk

• Determine mode of action when tumours observed
• Non-threshold (linear)
  • Default approach when mode of action is mutagenic or when adequate data not available/inadequate to support non-mutagenic mode of action
  • Linear low-dose extrapolation model (Q*)
• Threshold (nonlinear)
  • Mode of action has been clearly established with acceptable data supporting point of departure
  • Identify NOAEL/LOAEL; ensure adequate margin

Re-evaluation versus New Products

• Approach and data requirements are the same
• In re-evaluation, toxicology data packages may not be up to current standards in terms of quality and completeness
• Certain information more likely to be available for products under re-evaluation
  • Foreign reviews, epidemiology studies, incident reports, literature information

Summary - Overall Hazard Assessment Multi-Step Approach

• Hazard characterization
  • Identify adverse effects/target organs
  • Evaluate dose response
  • Identify NOAEL/LOAEL
• Integration of toxicology information
  • Cross-species comparison
  • Identify most sensitive species
• Assess relevance to humans
• Determine reference doses for each exposure scenario

References/Links

• Regulatory Directive DIR2005-01, Guidelines for Developing a Toxicological Database for Chemical Pest Control Products
• Regulatory Directive DIR2001-02, Guidelines for the Registration of Microbial Pest Control Agents and Products
• Regulatory Proposal PRO2002-02, Guidelines for the Research and Registration of Pest Control Products Containing Pheromones and Other Semiochemicals
• Regulatory Proposal PRO2007-02, Guidelines for the Registration of Low-Risk Biochemicals and Other Non-Conventional Pesticides
• Science Policy Note SPN2000-01, A Decision Framework for Risk Assessment and Risk Management in the Pest Management Regulatory Agency
• Regulatory Directive DIR98-01, Good Laboratory Practice
• Regulatory Directive DIR2006-02, Formulants Policy and Implementation Guidance Document
• Notice of Intent NOI2005-01, List of Pest Control Product Formulants and Contaminants of Health or Environmental Concern under the New Pest Control Products Act
• PMRA DACO Tables