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