JAS Toxicity

7/31/2019 JAS Toxicity

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Prof. J.A. Swenberg, DVM, PhD

Dept Environmental Sciences and Engineering

Rosenau [email protected]


2/27

Acute Toxicity Studies

Single dose - rat, mouse (5/sex/dose), dog,

monkey (1/sex/dose)

14 day observation

In-life observations (body wt., food

consumption, clinical observations)

Necropsy


3/27

Acute Toxicity Studies

Repeated dose studies - rat, mouse (5-

10/sex/dose), dog, monkey (2/sex/dose)

In-life observations

Necropsy

Histopathology

Clinical pathology (optional)


4/27

Acute LD50 Values vs Toxicity

Chemical

______________________________________

LD50 (mg/kg)

_________________

Toxicity

_________________

Sodium chloride 4000 Slightly toxic

DDT 100 Moderately toxic

Picrotoxin

StrychnineNicotine

5

21

Highly toxic

Dioxin

Botulinum toxin

0.001

0.00001

Super toxic


5/27

Subacute Toxicity

28 day study (3 doses and control)

Species - rat (10/sex/dose), dog or monkey

(2/sex/dose)


Clinical pathology

Necropsy

Histopathology


6/27

Subchronic Toxicity

13 week study +/- 4 wk recovery (3 dosesand control)

Species - rat (10/sex/dose), dog or monkey(2/sex/dose)

In-life observations (+/- ophthamology)

Clinical pathology Necropsy

Histopathology


7/27

Carcinogenicity Study

2 years (3 doses and control)

Species - rats and mice (50/sex/dose)


Clinical pathology (rats, optional)

Necropsy Histopathology


8/27

Carcinogenicity Study Evaluation

Issues

Survival

Body weight Variability of

endpoints

Pathology Working

Group

MTD

Statistics vs biology Dose-response

Mechanistic factors


9/27

MTD ISSUE

The Maximum Tolerated Dose is defined

as the highest dose of a chemical or drug

that can be administered for the animalslife without causing excessive toxicity or

decreasing survival (except due to tumor

induction).


10/27


11/27

MTD Debate I

Normal physiology, homeostasis and

detoxification or repair mechanisms may

be overwhelmed and cancer, whichotherwise might not have occurred, is

induced or promoted.

OSTP, 1985


12/27

MTD Debate II

More than two-thirds of the

carcinogenic effects detected in feeding

studies would have been missed had thehigh dose been reduced from the

estimated MTD to 1/2 the MTD.

Haseman, FAAT, 1985


13/27

MTD Issue

The problem is not testing for

carcinogenic potential at the Maximum

Tolerated Dose, it is how those data areused in risk assessment. The proper

interpretation and use requires an

understanding of the mechanism(s) ofaction.


14/27

Overview

The integration of metabolism, toxicity,

pathology and mechanism is playing a

much greater role today than ever before.A better understanding of these areas is

essential for proper regulation of

chemicals and drugs. It can also play animportant role in the development of

backup drugs and chemicals.


15/27

Bradford Hill Criteria

for Cancer Causation

Consistency

Strength

Specificity

Temporality

Coherence

Dose Response

Biological

Plausibility

Experimental

Support Analogy


16/27

1986 EPA Cancer Risk Assessment Guidelines

i h i i f h i


17/27

Systematic Characterization of ComprehensiveExposure-Dose-Response Continuum and the Evolutionof Protective to Predictive Dose-Response Estimates


18/27

IPCS/EPA Framework for

Evaluating Mechanistic Data Introduction

Postulated mode of

action

Key events

Dose-response

relationship

Temporal association Strength, consistency

and specificity of

association with key

events

Biological plausibility

and coherence

Other modes of action

Assessment of mode of

action

Uncertainties,

inconsistencies and datagaps


19/27

General Approaches To Risk Assessment

Qualitative approach using scientific judgment

Quantitative approach using safety factors

Quantitative approach using mathematical models

Quantitative approach using linear extrapolation


20/27


21/27

Human

EPI

Data

Where the

Question ofHealth Risk is

Raised

Respo

nse

Log Dose

Paustenbach (1995

Animal

Data


22/27

Cancer Risk Assessment

Population risks for environmental

carcinogens are usually set at one additional

cancer per 100,000 or 1,000,000 individuals

Occupational risks are frequently much

higher, with one additional cancer per 1,000workers being not uncommon


23/27

Hazard Identification

A qualitative risk assessment

Does an agent have the potential to increase

the incidence of cancer under any

conditions


24/27

Dose-Response Assessment

The relationship between dose and response

(cancer incidence)

Two sets of data are usually available

Data in the observable range

Extrapolation to responses below the

observable range


25/27

Exposure Assessment

EPA uses the cumulative dose received over

a lifetime

This is expressed as the average daily

exposure

Occupational exposures are usually basedon exposure during the work week


26/27

Risk Characterization

Provides an overall conclusion and confidence of

risk for the risk manager

Gives the assumptions made

Explains the uncertainties

Outlines the data gaps


27/27

Helpful Web Sites

www.epa.gov/ncea/

www.fda.gov/cder/

www.ovpr.uga.edu/qau/

Documents

JAS Toxicity