Health Consequence Scoring for Chemical Contaminants in Animal Feed

Karen Ekelman, Ph.D. 
AFSS Public Meeting
September 12, 2006

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Outline

• Review and Background
• Health Consequence Scoring for Chemical Feed Contaminants
  • Acute Adverse Effects
    • Severity Scores
    • Potency Scores
    • Examples
  • Chronic Adverse Effects
    • Severity Scores
    • Potency Scores
    • Examples

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Review: AFSS Relative Risk Model

• Goal: The AFSS Relative Risk Model is a tool for ranking relative risks of feed contaminants to aid FDA in setting priorities for allocating its resources in a risk-based manner
• Relative Risk Score = Health Consequence Score (HCS) x Exposure Score (ES)
• Health Consequence Score (HCS) = Severity Score (SS) x Potency Score (PS)

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Review: AFSS Relative Risk Model

• Reminders:
  • The list of potentially harmful feed contaminants should not be considered to be the definitive list of feed contaminants that pose a significant risk to animal or human health
    • Some items on the list may turn out to pose very low relative risks to animal or human health
    • Some items may need to be added to the list
  • Health Consequence Scores for contaminants are not Relative Risk Scores (Exposure is missing)

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Review: AFSS Relative Risk Model

• Health Consequence Scores (HCS) for chemical and biological contaminants will be developed for:
  • Appropriate species:
    • Food-producing animals such as cattle, swine and chickens
    • Pets such as dogs and cats
    • Humans
  • Specific exposure scenarios:
    • Acute and chronic exposures for chemicals
    • Acute exposures for biological contaminants

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Chemicals: Acute Adverse Effects

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Chemicals: Acute Adverse Effects

• Acute adverse effects occur following a single or short-term exposure to a toxic dose of a chemical
  • Acute adverse effects may be:
    • Easily identified by trained or untrained observers (death, seizures, vomiting), or
    • Identified only after laboratory examination of affected tissues and organs
  • Acute adverse effects may occur
    • Immediately after exposure, or
    • Be delayed

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• Chemicals: Acute Adverse Effects
  • Data on acute adverse effects come from:
    • Results of accidental or deliberate poisonings in humans and animals (anecdotal reports)
    • Data from acute toxicity tests conducted on animals

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Chemicals: Acute Adverse Effects

• Most acute toxicity test data on chemicals come from the LD₅₀ test (LD = Lethal Dose)
  • LD₅₀ is the amount of a chemical given in a single dose that causes the death of 50% of a group of test animals; can be measured or extrapolated
  • Most are conducted in rodents, so results need to be extrapolated to other species
  • Oral LD₅₀ results are most relevant
  • LD₅₀ is usually measured in mg of the chemical per kilogram of body weight of the test animal

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Chemicals: Acute Adverse Effects

• Acute Health Consequence Score =
  • Acute Severity Score x Acute Potency Score
• Acute Severity Scoring
  • The Acute Severity Scores for chemicals are numerical scores assigned to a chemical based on the types of effects observed in relevant acute toxicity studies or data from other sources
  • The Acute Severity Score for a chemical is based on the most severe (worst) effect observed in all studies used to assess the acute toxicity of the chemical

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Chemicals: Acute Adverse Effects

Severity Scoring for Acute Adverse Effects

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Chemicals: Acute Adverse Effects

• Acute Health Consequence Score =
  • Acute Severity Score x Acute Potency Score
• Acute Potency Scoring
  • Acute Potency Scores are numerical scores assigned to a chemical based on the measured or extrapolated doses that killed 50% of the test animals after administration of a single dose of the chemical (e.g. the LD50 value)
  • For chemicals with more than one reported LD50 value, the lowest value is used to determine the Acute Potency Score for the chemical
  • Acute Potency Scores may need to be adjusted for known species differences in sensitivity to a chemical

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Chemicals: Acute Adverse Effects

Acute Chemical Potency Scores are assigned based on three 1/LD50 ranges:

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Chemicals: Acute Adverse Effects

• Acute Potency Scoring (cont.)
  • To incorporate information from acute toxicity studies other than LD50 reports, a weight-of-the-evidence approach will be used to assign the study results to the appropriate potency category, using:
    • Information for chemicals with related chemical and physical properties
    • Information for chemicals with similar toxicity profiles

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Example: Health Consequence Scores for Acute Adverse Effects of 16 Chemical Contaminants

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Example: Severity Scoring for Acute Adverse Effects

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Example: Potency Scoring for Acute Adverse Effects

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Acute HCS: 16 Chemicals

Health Consequence Scoring (HCS) for Acute Adverse Effects

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Acute HCS: 16 Chemicals

Health Consequence Scoring (HCS) for Acute Adverse Effects

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Acute HCS: 16 Chemicals

Health Consequence Scoring (HCS) for Acute Adverse Effects

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Health Consequence Scoring (HCS) for Acute Adverse Effects

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Example: Ranking of 16 Chemicals by Acute Health Consequence Scores (HCS)

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Chemicals: Chronic Adverse Effects

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Chemicals: Chronic Adverse Effects

• Chronic toxicity occurs when a toxic dose of a chemical is consumed for a significant portion of the subject’s lifetime
• Chronic toxicity data can come from:
  • Long-term studies in humans (epidemiological studies)
  • Long-term studies in laboratory animals

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Chemicals: Chronic Adverse Effects

• The following set of studies is usually used to determine the chronic toxicity of a chemical:
  • Chronic toxicity studies
  • Carcinogenicity studies
  • Reproductive toxicity studies
  • Developmental toxicity studies
• Fewer or shorter studies on a chemical result in greater uncertainty in estimating its chronic toxicity

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Chemicals: Chronic Adverse Effects

• Chronic Health Consequence Score =
  • Chronic Severity Score x Chronic Potency Score
• Chronic Severity Scoring
  • The Chronic Severity Score is a numerical score assigned to a chemical based on the types of effects observed in chronic toxicity studies or from other data sources

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Chemicals: Chronic Adverse Effects

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Chemicals: Chronic Adverse Effects

• Chronic Health Consequence Score =
  • Chronic Severity Score x Chronic Potency Score
• Chronic Potency Scoring for effects other than cancer
  • A Chronic Potency Score is assigned to a chemical based on the most severe (worst) effect observed in all studies used to assess the chronic toxicity of the chemical
  • Basis for the Chronic Potency Score is an estimate of an Acceptable Exposure Level (AEL) for each chemical contaminant

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Chemicals: Chronic Adverse Effects

• The AEL (Acceptable Exposure Level) is an estimate of the amount of a chemical that can be ingested daily over a lifetime without an appreciable risk of adverse effects
  • AEL is analogous to EPA’s reference dose (RfD) and FDA’s Acceptable Daily Intake (ADI)
  • The AEL is usually expressed on a body weight basis (e.g., mg/kg body weight/day)
  • AEL is determined according to standard methods for deriving RfDs and ADIs

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Chemicals: Chronic Adverse Effects

• To calculate an AEL (Acceptable Exposure Level):
  • Determine the NOEL (No Observed Effect Level) or NOAEL (No Observed Adverse Effect Level) for each study used to determine the chronic toxicity of the chemical
  • Divide each NOEL or NOAEL by appropriate safety factors (SF); this number is an AEL
  • The lowest AEL calculated from studies used to determine the chronic toxicity of a chemical is the AEL assigned to the chemical

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Chemicals: Chronic Adverse Effects

Safety Factors

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Chemicals: Chronic Adverse Effects

• The Chronic Potency Score for non-cancer endpoints is determined by placing the inverse of the AELs (1/AEL) for all chemical contaminants on a comparative scale
  • Scale in then divided into 3 categories
  • Each category is assigned a Chronic Potency Score
• Acute Potency Scores may need to be adjusted for known species differences in sensitivity to a chemical

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Chemicals: Chronic Adverse Effects

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Chemicals: Chronic Effects

• Chronic Potency Scoring for cancer effects
  • One measure of carcinogenic potency is the estimated dose associated with a one in one million lifetime risk of cancer (Lifetime Cancer Risk)
    • For cancer-causing chemicals with estimated one in one million lifetime risk doses, those estimates will be used to determine the Chronic Potency Score using a scale similar to the one established for the non-cancer chronic effects

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Chemicals: Chronic Adverse Effects

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Chemicals: Chronic Adverse Effects

• Chronic Potency Scoring for cancer effects (cont.)
  • For cancer-causing chemicals without estimates of a one in one million risk dose, a weight-of-the-evidence approach will be used to assign the chemical to the appropriate potency category, based on
    • Analyses by various regulatory bodies
    • Information on chemicals with related chemical, physical or toxicological properties

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Example: Health Consequence Scores for Chronic, Non-Cancer Adverse Effects of 14 Pesticides

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Example: Severity Scoring

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Example: Potency Scoring

a Weighting of scores can be changed 

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Example: 14 Pesticides (1)

Health Consequence Scoring (HCS) for Chronic Adverse Effects

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Example: 14 Pesticides (2)

Health Consequence Scoring (HCS) for Chronic Adverse Effects

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Example: 14 Pesticides (3) Health Consequence Scoring (HCS) for Chronic Adverse Effects

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Example: Ranking of 14 Pesticides by Chronic, Non-Cancer Health Consequence Scores (HCS)

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Chemical and Physical Contaminants: Summary

• Health Consequence Score (HCS) x Exposure Score (ES) = Relative Risk Score
• HCS = Severity Score x Potency Score
  • SS = Severity Score
    • Acute Effects SS for Chemicals
    • Chronic Effects SS for Chemicals
  • PS = Potency Score
    • Acute Effects PS for Chemicals
    • Chronic Effects PS for Chemicals
• Need to develop a weighting scheme for Acute HCS, Non-cancer Chronic HCS and Cancer HSC scores