Introduction to Toxicology
EV 460/660 & BI 460/660
Fall 2014
Factors Affecting Toxicity
1.
DOSE – remember Paracelsus
-- dose vs. dosage
- -external (nominal) dose vs. internal (target tissue) dose
-- target tissue concept
-- scale of relative toxicity of compounds
2.
Duration of exposure -- and frequency/pattern of exposure
-- trade-offs between dose and duration
-- acute, subacute, subchronic, chronic, lifetime, multigenerational
-- acute vs. chronic effects
-- misunderstood rationale for high dose testing in lab animals
-- frequency/pattern of exposure will affect kinetics (see below)
-- variations on duration of exposure may be linked to age (see below)
3.
Route of exposure
-- dramatically affects toxicity due to kinetics (see below)
-- variety of common routes – oral, inhalation, dermal, ocular, in utero
-- variety of experimental/clinical routes – oral (p.o.), inhalation, dermal (topical, s.c.),
i.v (intravenous), i.p. (intraperitoneal), i.m. (intramuscular), i.c. (intracranial),
i.t. (intrathecal), and others
-- general rule of thumb on toxicity: i.v. > inhalation > i.p. > s.c. > i.m. > oral > dermal
4.
Species
--enormous determinant of toxicity, potent poison for one species may be relatively harmless to
another
-- tremendous difficulties in inter-species extrapolation of toxicity data
5.
Genetic Variability within species
-- some strains or individuals will be more/less sensitive
-- use of highly inbred strains of laboratory animals
-- safety margins for calculation/estimation of “safe” levels
-- some evidence for ecological selection occurring in contaminated environments
6.
Age & Developmental Stage at time of exposure
--embryo, fetus, infant, child, young adult, adult, old adult
-- general rule of thumb on toxicity: youngest and oldest are most at risk
youngest – embryonic and fetal development, organogenesis, fetal growth
-- early postnatal – sometimes higher absorption, less developed detoxification
and excretion mechanisms, less developed anatomic “barriers”, e.g. BBB
oldest – declining effectiveness of detoxification and excretion mechanisms, host of
physiological and pathophysiological changes with aging
-- traditionally – lab tests of toxicity conducted with young adult animals (most resistant)
-- thalidomide tragedy – forced attention to pre-natal exposures, currently considerable efforts
at assessing toxicity in youngest ages
-- oldest age group still neglected – sheer practical difficulties involved
7.
Chemical Form and related chemical properties
-- effect on kinetics (see below)
-- lipid solubility – differences in absorption, ease of passage through biological membranes,
storage in adipose tissues, etc.
-- same poison can vary widely in toxicity depending on chemical form – ex. elemental metal,
metal salt (salt solubilities /toxicities vary), metallic vapor, organo-metallic compounds
8.
Gender or sex of the organism
-- often not an important variable for many poisons
-- may be a very important variable for select poisons due to gender-related differences in
hormonal and metabolic processes
9.
Nutritional Status
-- influence may be non-specific, general rule of thumb is poor diet leads to higher sensitivity
to poisons
-- influence may be non-specific – ex.- impairment of hepatic functions
-- influence may be nutrient and poison specific – competition for absorption or critical
nutrients required for detoxification mechanisms
-- traditional laboratory toxicity tests conducted with animals living on super-fortified diets
10.
Concomitant Disease or pre-existing or co-occurring pathophysiological conditions
--may be non-specific as a generalized stressor (see below)
-- may be non-specific as alterations in overall kinetics (see below)
-- may be specific to the poison and the target organ system
11.
Stressors
-- Hans Selye – stress and the General Adaptation Syndrome
-- generalized stressors – ex. temperature, humidity, photoperiod, social crowding/isolation
-- general rule of thumb is more stress leads to higher sensitivity to poisons
12.
Prior Exposure History
-- sensitization – immunologic reactions, up regulation of receptors
-- tolerance – hepatic enzyme induction, down regulation of receptors
13.
Chemical Interactions
-- generic forms of interactions – additive, potentiation, synergism, antagonism
-- real-world importance
-- toxicity of complex chemical mixtures poorly understood and a great challenge for the future
14.
Toxicokinetics
-- tremendous impacts on toxicity
-- next major topic