Last updated on 9/11/01

INTRODUCTION •

DEFINITIONS

TOXICOLOGY: The study of the adverse effects of chemicals on living things. As defined by techniques and purpose: regulatory, biochemical, clinical, descriptive, forensic. As defined by focus: immuno-, neuro-, developmental, respiratory. ENVIRONMENTAL TOXICOLOGY: The study of the adverse effects of chemicals found in the environment on living things. These are generally man-made OR man-manipulated chemicals (exception - RADON). ECOTOXICOLOGY: The study of the adverse effects of chemicals on ecosystems or populations within an ecosystem. NOTE: chemical = toxicant* = xenobiotic = toxin* = poison | drug = ligand [x] = concentration of x *By definition, toxin is a naturally derived, naturally exposed toxic chemical (e.g., snake venom) whereas toxicant is either of manmade origin (e.g., organophosphate pesticides) or of natural origin but manipulated, concentrated or dispersed by humans (e.g., lead or pyrethrin pesticides). PRIMARY MESSENGERS: The major chemicals used to communicate between cells. The most common 1o messengers are termed neurotransmitters (nervous system – released from neurons), hormones (endocrine system – released by endocrine cells), cytokines (immune system), growth factors and other homeostatic control chemicals (no specific source system). RECEPTORS: The receptor receives information or is exposed to the toxicant and reacts/responds. Cellular: A molecule, usually protein-based, that interacts with the primary messengers of the body. Three types: membrane, cytoplasmic, nuclear, defined by location in the cell. Membrane receptors typically interact with amino acid-based or polypeptide/protein chemicals. Environmental: The target organism for a given chemical. This is the term used in risk assessment and is based on the analogy with the cellular receptors. Sensory: A specialized type of neuronal cell that detects incoming sensory information and transduces it (i..e. translates it) into chemical information that can be detected by other cells in the nervous system.

Tox Notes by D. Henshel for use in E410/E520 as study aids.

Last updated on 9/11/01

SECOND MESSENGERS: Second messengers are ions (ex: Ca++) or other small intracellular molecules (ex: cGMP, cAMP, IP3) that mediate the response of the primary extracellular messenger within the cell. Second messenger systems vary, but may include a cascade of phosphorylating enzymes, for example, or the opening of channels (such as calcium channels) in the membrane of the cell or of intracellular calcium storage organelles. (Note : these are just two of multiple examples.) SUBSTRATE: A substance upon which an enzyme (or chemical) acts. This is a cellular effect. TARGET ORGAN (OR TISSUE): The organ or specific tissue where or in which a toxicant causes an adverse effect. QUANTAL RESPONSES: All-or-none (or quantified) responses generally used for population data. Ex: death, tumors; or, quantified, graded responses. GRADED RESPONSES: Responses which vary continually with dose, generally used when assessing individual responses to a toxicant. Ex: change in body temperature. TOXIC END POINT: Biological effect used to measure a toxic response. Ex: death, tumors, enzyme activity, membrane potential. DOSE: Amount of chemical given to or taken up by the organism. DOSAGE: Dose corrected for size of the organism by dividing by body weight or surface area. DOSE-RESPONSE CURVES: Dose is plotted against a quantified response (the 'end point') and the toxicity of the substance depends on the dose (typically, but not always, ↑ dose → ↑ response). See Figs. 2-3 and 2-4 Casarett and Doull (C&D; Klaassen, ed) 5th edition or Figs. 4-1 and 6-1 Lu 3rd edition. POTENCY: The power of an agent to produce the measured effect. This refers to the range of doses over which the chemical produces increasing responses. The lower the dose required to produce a given response, the more potent the chemical (Fig. 2-7 C&D 4th edition = Fig 2-8 C & D 5th edition). To evaluate potency, look at the x axis of the doseresponse curve. EFFICACY: How effective the chemical is at producing the measured response. This refers to the maximal effect elicited by the chemical. The larger the maximal response, the more effective the chemical is at producing that response (Fig 2-7 C&D 4th edition = Fig 2-8 C & D 5th edition). To compare efficacy look at the y axis of the dose-response curve. NOTE: DOSE per se DOES NOT DETERMINE TOXICITY. TOXICITY IS DETERMINED BY THE [ ] [i.e. concentration] OF THE TOXICANT AT THE TARGET ORGAN. ([ ] at the target organ is determined by the DISPOSITION of the chemical).

Tox Notes by D. Henshel for use in E410/E520 as study aids.

Last updated on 9/11/01

LD: Lethal dose – endpoint is death. LDX: Dose at which X% of the exposed population dies. LD50 (Lethal Dose 50): Dose at which 50% of the exposed population (above baseline levels) dies. TD: Toxic dose – endpoint is clearly adverse to the health of the individual or the population (e.g., tumors). ED: Effective dose – endpoint which may or may not reflect a clearly adverse effect (e.g., change in body temperature). LC/TC/EC: Lethal/toxic/effective concentration – used when evaluating toxicants in water or air. THRESHOLD DOSE: Concentration at and below which no measured effect is clearly (usually statistically significantly) distinguishable in the dosed versus the control population. Some chemicals are thought NOT to have a threshold, but elicit a measurable response at any dose. SATURATION: Dose at which 100% of test subjects respond or at which the response is maximized. NO(A)EL: No (Adverse) Effect Level – highest concentration at which no statistically significant effect is detectable compared to controls. LO(A)EL: Lowest (Adverse) Effect Level – lowest concentration at which there IS a statistically significantly distinguishable effect when the dosed population is compared to the control population. SAFE HUMAN DOSE = Threshold * Body Weight Safety Factor Safety factors may vary from <10 to 10,000 (usually 10-1000). Determining the safety factor depends upon professional judgement and the quality and extent of the data. •

WHAT AFFECTS A TOXIC RESPONSE?

1. Route/Site of Exposure (relative to the type of toxicant) 2. Duration/Frequency of Exposure Acute ≤ 24 hrs (~ 4 hrs for testing of gas toxicity) Subacute ≤ 1 month Subchronic > 1 month & ≤ 3 months

Tox Notes by D. Henshel for use in E410/E520 as study aids.

Last updated on 9/11/01

Chronic > 3 months (OR an approximate lifetime for some animal tests, i.e. 2 years for chronic rat toxicity tests) NOTE: NET EXPOSURE = [ ] X TIME 3. Single versus Multiple Exposure 4. Elimination Rate versus Frequency of Exposure (Figure 2-1, C&D 4th edition) 5. Species/Strain/Individual Variation (Tables 4-18, 4-19 C&D 4th edition) 6. Age of Animal (Table 5-1 C&D 2nd edition) 7. Nutritional/Health Status (Table 4-21 C&D 4th edition) 8. Physiochemical properties of the test compounds - molecular weight and formula, structural formula, whether it’s an electrophile or neutrophile, acidity/alkalinity, particle characteristics, density, corrosivity, water and lipid solubility, melting point, boiling point, vapor pressure, dissociation constant (pK), stability at various pH values, stability to heat and light… •

TYPES OF TOXIC INTERACTIONS

1. Immediate versus Delayed toxicity Immediate: headache, rash Delayed: cancer, neuropathy 2. Reversible versus Irreversible effects Reversible: liver damage Irreversible: CNS damage 3. Local versus Systemic reactions Local: skin, GI, respiratory Systemic: most internal organs NOTE: Systemic reactions require entrance into the body, usually into the bloodstream. 4. Allergic reactions/Chemical sensitivity Hypersensitivity versus Hyposensitivity: varies by individual according to genetic makeup and past experience Local versus Systemic reactions: local = hives; systemic = anaphylactic shock Immediate versus Delayed reactions: rashes, asthma can be immediate or delayed

Tox Notes by D. Henshel for use in E410/E520 as study aids.

Last updated on 9/11/01

5. Chemical Interactions ADDITIVE: 2 + 3 = 5 (organophosphates [OPs]) SYNERGISTIC: 2 + 2 = 20 (carbon tetrachloride [CCl4] & ethanol [EtOH]) POTENTIATION: 0 + 2 = 10 (Isopropanol & carbon tetrachloride) ANTAGONISM: 4 + 6 = 8, 4 + (-4) = 0, 4 + 0 = 1 Types of Antagonism: functional: affects same physiological function (estradiol and methoxychlor; nitric oxide [NO] and antidiuretic hormone [ADH]) chemical: chemical interaction with toxin to produce less toxic product, i.e. chelators of metal ions (lead [Pb] and EDTA) dispositional: affects the disposition of the toxin, typically resulting in reduced effective [ ] at target organ (EtOH decreases methanol toxicity) receptor: blocks receptor activation process → acts on same binding site OR → acts on different binding site of the same receptor (spironolactone and aldosterone)

"All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy." Paracelsus (1493-1541)

Tox Notes by D. Henshel for use in E410/E520 as study aids.

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