EHS 507 Potential dose: the amount of chemical that is ingested or inhaled, or the amount of chemical contained in material applied to skin. Applied dose: the amount of chemical available at the absorption barrier (skin, lung, GI tract). Potential dose and applied dose

EHS 507 Internal dose definitions  Internal dose: the amount of chemical that has been absorbed and is available for interaction with biologically significant receptors (e.g., target organs)  Delivered dose: the amount transported to an individual organ, tissue, or fluid of interest  Biologically effective dose (BED): the amount that actually reaches cells, sites, or membranes where adverse effects occur –may represent only a fraction of the delivered dose –the best for predicting adverse effects

EHS 507 The Continuum From Emission of a Contaminant (adverse agent) to a Health Effect Transport and transformation Contaminant source emissions Accumulation in environment Human contact: exposure Potential dose to body Early expression of disease Health Effect Biologically effective dose Internal dose

EHS 507 Potential Dose Applied Dose Absorbed Dose Delivered Dose Biologically Effective Dose (BED) Skin Surface Bloodstream Target Organ Target Cells Exposure and Dose Concepts and Terms

EHS 507 The Continuum From Emission of a Contaminant (adverse agent) to a Health Effect (Lioy, P. Env. Sci. Tech. 24, 7, 1990, ) Transport and transformation Contaminant source emissions Accumulation in environment Human contact: exposure Potential dose to body Early expression of disease Health Effect Biologically effective dose Internal dose Animation (do not print)

EHS 507 Transport and transformation Contaminant source emissions Accumulation in environment Human contact: exposure Potential dose to body Early expression of disease Health Effect Biologically effective dose Internal dose Bioavailability Pharmacodynamic models The Continuum From Emission of a Contaminant (adverse agent) to a Health Effect Applied dose Delivered dose Pharmacologically-based pharmacokinetic (PBPK) models Distribution Transformation Storage Excretion Animation (do not print)

EHS 507 Transport and transformation Contaminant source emissions Accumulation in environment Human contact: exposure Potential dose to body Early expression of disease Health Effect Biologically effective dose Internal dose Distribution Transformation Storage Excretion Bioavailability Applied dose Delivered dose Pharmacodynamic models Pharmacologically-based pharmacokinetic (PBPK) models The Continuum From Emission of a Contaminant (adverse agent) to a Health Effect

EHS 507 The Continuum From Emission of a Contaminant (adverse agent) to a Health Effect Transport and transformation Contaminant source emissions Accumulation in environment Human contact: exposure Potential dose to body Early expression of disease Health Effect Biologically effective dose Internal dose

EHS 507 Key Routes of Chemical Absorption, Distribution and Excretion (US OTA, 1981)

EHS 507 Integrated or aggregate or cumulative exposure is the sum total of exposure to a chemical via all routes of exposure (and all media) over a specified time period The units of integrated exposure are concentration multiplied by period of time. Integrated exposure is the total “area under the curve” (AUC) of the exposure profile. Exposure and dose relationships

EHS 507 Concentration mg/m 3 Absorption Rate mg/hr Time (yr) Time (hr) Exposure = Conc. x Time Dose = Absorption Rate x Time = (mg/m 3 ) x yr = (mg/hr) x hr = mg Exposure versus dose =

EHS 507 Time-weighted average (TWA) concentration: the integrated exposure divided by the period during which exposure occurs. TWA dose rate: the total dose divided by the time period of dosing –usually expressed in units of mass per unit time, or mass/time normalized to body weight (e.g., mg/kg-day). Exposure and dose relationships (cont.)

EHS 507 Conc. Time Exposure = Conc. x Time TWA Concentration = Exposure Time period of exposure TWA Dose = Total dose Time period of dosing Mass / Body wt. Time mg kg-day = = mg m 3 = Calculating Time Weighted Averages (TWAs)

EHS 507 Classification of exposures based on duration Duration: the period of time over which the person is exposed Acute exposure: generally involves one contact with the chemical; usually for less than a day Chronic exposure: exposure takes place over a substantial portion of a person’s lifetime Subchronic (or subacute) exposure: exposures of intermediate duration

CHRONIC GENERAL VARIABILITY OF CHRONIC EXPOSURE TO ENVIRONMENTAL AGENTS FREQUENCY TWA EXPOSURE INTENSITY MEDIAN LOG-NORMAL DISTRIBUTION

EXPOSURE HISTORY The temporal history of the exposure intensity over the lifetime of the exposed population or individual, for example:- TIME (years) EXPOSURE actual exposure the best we can estimate (often)