Dose - Response Relationships

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Understand the quantitative relationship between toxicant exposure and induced effects. • Describe frequently encountered toxic effects. • Interpret frequency (normal distribution) and dose response curves. • Understand threshold effects with dosage increase.

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Principles of Environmental Toxicology Learning Objectives • Understand the quantitative relationship between toxicant exposure and induced effects. • Describe frequently encountered toxic effects. • Interpret frequency (normal distribution) and dose - Dose - Response Relationships response curves. • Understand threshold Principles of Environmental Toxicology effects with dosage increase. Instructor: Gregory Möller, Ph.D. University of Idaho 2 Principles of Environmental Toxicology Principles of Environmental Toxicology Learning Objectives, 2 What is a Dose? • Understand effective dose, margin-of-safety and • The amount of a substance administered at the relationship of effective vs. toxic dose. one time. • Examine the use of actual data for no observed • Dosage is the amount per unit weight of the effect and lowest observed exposed individual. effect in risk assessments. • Exposure is characterized • Summarize effective, lethal by and toxic doses. – Number of doses – Frequency of dosing • Understand a linearized – The total period of time multi-stage model for for the exposure. non-threshold responses. 3 4 Principles of Environmental Toxicology Principles of Environmental Toxicology Quantifying the Dose Key Concepts • Dosage - response mathematical relationship • Gram (g) is the standard unit but mg is typical of most exposures in toxicology. (positive slope). • Dosage: mg (dose) / kg (bw) / day (duration) • Causal relationship. – mg/kg/d • Observable responses. • Exposures are quantified in relation to the • Statistical management of variability media. of individual responses. – mg/L in water. – Species, genetics, age, sex. – mg/kg in food. – mg/m3 in air. • Variation in units common (ppm, ppb). 5 6 1
Principles of Environmental Toxicology Principles of Environmental Toxicology Responses (Toxic Effects) Responses (Toxic Effects), 2 • Inflammation. • Lethal synthesis. – Local or systemic response. – Toxicant incorporation into a biochemical pathway. • Necrosis. • Lipid peroxidation. – Cell or tissue death. – Free radical oxidation of fatty acids leading to cell death. • Enzyme inhibition. • Covalent binding. – Biochemical pathway interruption. – Of electrophilic reactive – Competitive; non-competitive. metabolites to nucleophillic • Biochemical uncoupling. macromolecules. – Interference with phosphate molecule synthesis (ATP) 8 Ballantyne 7 Principles of Environmental Toxicology Principles of Environmental Toxicology Responses (Toxic Effects), 3 Responses (Toxic Effects), 4 • Receptor interaction. • Neoplasia. – Modification of normal biological effects mediated – Aberrant cell division and tissue growth. by the receptor. • Neoplasms: tumorigenesis, oncogenesis. • Immune-mediated hypersensitivity reactions. • Malignant neoplasms: carcinogenesis. – Antigenic chemicals resulting in allergic reaction. • Immuno-suppression. – Increased susceptibility to infectious agents and tumorigenesis. 9 10 NLM Principles of Environmental Toxicology Principles of Environmental Toxicology Responses (Toxic Effects), 5 Types of Toxic Responses: Idiosyncratic • Genetically determined sensitivity or resistance to • Genotoxic interaction. toxicity – Chemical interaction with DNA possibly leading to – Usually lack of enzymes / factor involved in metabolism heritable change. • Primaquine (oxidative anti-malarial drug) - 10% • Clastogenic (chromosomal) effects. black males / erythrocyte G-6-P dehydrogenase / • Mutagenic (base pair) effects. hemolytic anemia • Developmental and reproductive toxicity. – Glucose-6-phosphate – Adverse effects on dehydrogenase deficiency, conception, and the most common enzyme structure and function deficiency worldwide of the conceptus. • Nitrites - lack NADH-methemoglobin reductase / methemoglobinemia 11 12 2
Principles of Environmental Toxicology Principles of Environmental Toxicology Dose-Response Types of Toxic Responses: Allergic • Immunological mediated response (memory) • Quantitative analysis of incremental dose increase and occurrence of toxic end effect • Requires sensitizing exposure • Responses follow normal frequency distribution • May involve chemical/protein complex (hapten) (Gaussian) • Atypical dose response – Small doses most effective – Large dose tolerance • Ts cells (suppressor T lymphocytes) • Contact dermatitis; anaphylaxis • Pollens, pesticides, sulfur, penicillin 13 14 Principles of Environmental Toxicology Principles of Environmental Toxicology Normal Distribution, 2 Normal (Gaussian) Distribution • Population representation of variability. 15 16 Principles of Environmental Toxicology Principles of Environmental Toxicology Normal Distribution Parameters Dose - Response Curve Resistant • Mean + one SD = 68.3 % population • Mean + two SD = 95.5 % population • Mean + three SD = 99.7 % population • Frequency converted to cumulative gives sigmoid curve Sensitive 17 18 3
Principles of Environmental Toxicology Principles of Environmental Toxicology Observed Effects Toxic Thresholds 19 20 Principles of Environmental Toxicology Principles of Environmental Toxicology Shape and Slope Median Lethal Dose LD50 Interpretation • Often used to compare toxicity • Only measures lethality • Best for quantal data • Best for acute exposure • Tells nothing about slope • Specific quantifiers 21 22 Principles of Environmental Toxicology Principles of Environmental Toxicology Comparative Toxicity Other Thresholds: ED90 – EC50 – LC10 – TDLo • ED: effective dose – Pharmaceuticals • EC: effective concentration – Pharmaceuticals in vivo • Often blood – Environmental toxicology • LC: lethal concentration – Environmental toxicology • TDLo: Lowest published toxic dose • TCLo: Lowest published toxic concentration 23 24 4
Principles of Environmental Toxicology Principles of Environmental Toxicology Therapeutic Index - TI Effective Dose • Ratio of dose to produce toxic effect to dose to produce desired effect • TI = LD50/ED50 • The larger the ratio, the greater the safety (e.g. 10) • Slope of dose response important Therapeutic Index (TI) = Toxic Dose/Therapeutic Dose 25 26 Principles of Environmental Toxicology Principles of Environmental Toxicology Margin of Safety Margin of Safety - MOS • Accounts more for slope differences • MOS = LD1/ED99 • Neither TI or MOS works for chemicals with no beneficial effect or repeated doses Margin of Safety (MOS) = LD(01)/ED(99) 27 28 Principles of Environmental Toxicology Principles of Environmental Toxicology Carcinogen Risk Assessment Linearized Multistage Model • Linearized Multistage Model – Assumes non-threshold effect. • Linear extrapolation through zero threshold dose from upper confidence level of lowest dose that caused cancer in animal study. • Analysis results in a cancer slope factor that can be used to predict cancer risk at a specific dose. NLM 29 30 5
Principles of Environmental Toxicology Principles of Environmental Toxicology Other Models for Risk Assessment Transformation of Variables • One hit model (cancer) • Allows better (simpler) analysis of data at points of interest such as LD50. – Assumes a molecular event with cellular response. • Transformation into an approximate normally distributed • Multi hit model (cancer) variable. – Assumes multiple events prior to cellular activation. • Examples (rj = dead animals; nj = total animals) • Probit model • Probit transformation. – Based on Gaussian (Bell) curve. – Linearization transformation that – Probit (rj/nj) = Φ-1 (rj/nj) assumes log normal distribution. – Useful in acute lethality tests. • PB PK - Physiologically based • Logit transformation. pharmacokinetic model – Log odds of a quantal response. – Logit (rj/nj) = ln [(rj/nj)/1 - (rj/nj)] – Uses intensive pharmacokinetic • Weibull transformation. and mechanistic data. – Exponential model used in modeling multistage processes. 31 32 Principles of Environmental Toxicology Principles of Environmental Toxicology Probit Transformation Probit Transformation, 2 • Probability units → “probits” % Response SD NED Probit 0.1 -3 -3 2 • Convert % response to units of deviation from the mean or “normal equivalent deviations” (NEDs). 2.3 -2 -2 3 • Hence the NED for a 50% response is 0. 15.9 -1 -1 4 • “Probit” approach adds 5 50.0 mean 0 5 to avoid negatives. 84.1 +1 +1 6 97.7 +2 +2 7 99.9 +3 +3 8 33 34 Principles of Environmental Toxicology Principles of Environmental Toxicology Probit Transformation, 3 Log Normal Distribution • Perform log10 transformation of the dose. – Assumes log normal distribution. • Produces an approximately linear relationship. – Allows linear regression analysis. 35 36 6
Principles of Environmental Toxicology Principles of Environmental Toxicology Probit Unit Transformation Summary: Transformations of D-R Curve • Normal frequency distribution • Arithmetic dose to log dose • Frequency data to cumulative • Probability of response to NED – Standard deviations of mean • NED to probit – NED + 5 37 38 Principles of Environmental Toxicology Principles of Environmental Toxicology Example: Acute & Chronic Ecotoxicology Tests Dose-Response Curve Summary Major Parameters • Allow for a relative indication of toxicity. – LC50 LD50 EC10 • Median Lethal Dose - LD50 – Assists in QSAR development. – Other LDs, TDs or EDs – WET: whole effluent toxicity. • Slope • Often simple, inexpensive. • Thresholds – Good reproducibility. • System saturations • Useful for defining environmental quality standards. • Comparative toxicity – Safety factor approach 1:100 • Risk assessment • Bacteria, algae, plants, invertebrates (i.e. insects), vertebrates (i.e. rats). 39 40 7