Reading Casarett and Doull Chapters 5 and 7 Timbrell, Chapter 3 EXPOSURE: Absorption, Distribution, Elimination. Or, how do chemicals (and microbes) get into, around and out of our bodies

Routes of Exposure Airborne – inhalation –Respiratory tract, nose-lungs Foodborne – ingestion –Gastrointestinal tract Skin Contact - transdermal Waterborne Injection –Wounds, needlesticks

The plasma membrane Lipid bilayer Polar Non-polar (Lipid) Protein Av. Width 7.5 nm (75 Å) Sugar Glycolipid Glycoprotein

Mechanisms of uptake Passive diffusion Filtration Carrier-mediated transport –Facilitated diffusion –Active transport Engulphment –Pinocytosis –Phagocytosis

Uptake Higher concentration Lower concentration Diffusion Filtration Pore Lipid bilayer Carrier Facilitated diffusion Active transport

Engulfment

Engulphment

Microbes Host cell receptors – glycolipids, glycoproteins or proteoglycans Microbial pili, fimbriae, adhesins – lectins, hemagglutinin

Factors influencing route and rate of uptake Properties of the chemical –Size and shape –Similarity to “endogenous” molecules –Solubility Hydrophilicity/hydrophobicity Lipophilicity/lipophobicity Partition coefficient: K ow –Log 10 of [octanol]/[water] –Charge Ionization state

For an acid: HAH + + A - –Henderson-Hasselbach equation: pH = pK ’ + Log 10 [A - ]/[HA] For a base: BH + B + H + –Henderson-Hasselbach equation: –pH = pK ’ + Log 10 [B]/[BH + ]

Properties of the membrane/tissue/organ –Presence/absence of pores –Presence/absence of carrier molecules –Thickness –Lipid content Factors influencing route and rate of uptake Carrier

Skin

Surface area approximately 2 m 2 Multilayered –Epidermis Stratum corneum Living epidermis –Dermis Blood circulation

Respiratory Tract

Respiratory tract Surface area approximately 50 to 100 m 2

Gastrointestinal tract Surface area approximately 600 m 2

Intestinal wall - villi

Cross-section of villus

Placenta

Distribution Factors affecting tissue localization Plasma proteins Barriers to distribution –Blood-brain barrier –Blood-nervous system barrier Factors that facilitate distribution –Sinusoids –Trans-membrane carriers

Location (In)ability to detoxify/clear infection Specific susceptibility – receptors, metabolic characteristics

Excretion Routes of elimination –Urine –Bile –Feces –Exhaled air –Sweat –Tears –Milk –Leaves

The Kidney

Lung again

Excretion Routes of elimination –Urine –Bile –Feces –Exhaled air –Sweat –Tears –Milk –Leaves