A Physiological Based Description of the Inhalation Pharmacokinetics of Styrene in Rats and Humans John C. Ramsey and Melvin E. Andersen Toxicology and Applied Pharmacology, 73(1), , (1984) Neil Geisler Final Project BIOEN May 2006

Neil Geisler -- BIOEN Final Project2 Impetus To understand and predict behavior of exogenous chemicals in the body Explain the relationship between blood concentration and air concentration of an inhaled chemical Extrapolate this relationship from experimental animals to humans

31 May 2006Neil Geisler -- BIOEN Final Project3 System Four components: –Highly perfused organs – RICHLY PERFUSED TISSUE –Moderately perfused tissue – MUSCLE –Slowly perfused tissue – FAT –Metabolizing tissue – LIVER

31 May 2006Neil Geisler -- BIOEN Final Project4 Model Styrene inhaled at a given concentration for a specified time, then normal ventilation continues Physiological pharmacokinetic model, including: –Uptake –Distribution –Metabolism –Excretion Scale up – Rat parameters proportional to human –Tissue volumes: 83 kg/0.30 kg = 277 –Blood flow: (290 liters blood/hr) / (5.64 liter blood/hr) = 51

31 May 2006Neil Geisler -- BIOEN Final Project5 Parameters BW = Body weight (kg) Q alv = Alveolar ventilation rate (liters air/hr) C inh = Concentration of styrene in inhaled air (mg/liter air) C alv = Concentration of styrene in alveolar air (mg/liter air) C exh = Concentration of styrene in exhaled air (mg/liter air) N = Blood:air partition coefficient (liters air/liter blood) Q t = Cardiac output (liters blood/hr) C art = Concentration of styrene in arterial blood (mg/liter blood) C ven = Concentration of styrene in mixed venous blood (mg/liter blood) V max = Maximum enzymatic reaction rate (mg/hr) K m = Michaelis constant for enzymatic reaction (mg/liter blood) Q i = Blood flow rate to tissue group (liters blood/hr) V i = Volume of tissue group (liters i) C i = Concentration in tissue group (mg/liter i) A i = Amount in tissue group (mg) dA m /dt = rate of metabolism of styrene (mg/hr) –A met = Amount of styrene metabolized (mg) C vi = Concentration in venous blood leaving tissue group (mg/liter blood) P i = Tissue:blood partition coefficient (liters blood/liter i) (i) includes the various tissue groups –l = liver (metabolizing tissue group) –f = fat tissue group –m = muscle (lean) tissue group –r = richly perfused tissue group

31 May 2006Neil Geisler -- BIOEN Final Project6 Parameters Pulmonary compartment –Ventilation and perfusion rates –Blood:air partition coefficient Tissue uptake and release –Blood:tissue partition coefficients Metabolizing tissue –Michaelis-Menton metabolism, controlled by V max and K m

31 May 2006Neil Geisler -- BIOEN Final Project7 Styrene ventilation Concentration equilibrium of styrene between alveolar air and arterial blood Blood:air partition coefficient Combining concentration equilibrium equation and partition coefficient After exposure ends, C inh goes to zero Concentration in exhaled air is a combination of alveolar and inhaled air

31 May 2006Neil Geisler -- BIOEN Final Project8 Styrene uptake, release, and metabolization in the tissue Time-dependent amount of styrene in each non-metabolizing tissue group Concentration of styrene in each group Concentration of styrene in venous blood leaving each tissue group Metabolism of styrene follows Michaelis-Menton type kinetics Styrene in metabolizing group combines rate of change of styrene in liver with metabolic rate of removal Concentration of styrene in the venous blood is the sum of the amount returning from each tissue group

31 May 2006Neil Geisler -- BIOEN Final Project9 Styrene concentration in arterial blood and fat of rats C art CfCf time (hours) 10e -3 10e -2 10e -1 10e 0 10e 1 10e Styrene concentration (mg/l)

31 May 2006Neil Geisler -- BIOEN Final Project10 Styrene concentration in arterial blood and exhaled air of humans C art C ex h time (hours) 10e -5 10e -4 10e -3 10e -2 10e -1 10e 0 10e Styrene concentration (mg/l)

31 May 2006Neil Geisler -- BIOEN Final Project11 Summary Sensitive to fat tissue group Sensitive to styrene metabolism Can scale-up from laboratory experiments to humans Styrene concentration controlled by –Saturation after inhaled styrene concentrations of 200 ppm in both rats and humans –Below 200 ppm, styrene concentration controlled by perfusion limited metabolism