Interspecies Extrapolation - ACS Symposium Series (ACS Publications)

3 Interspecies Extrapolation DANIEL B. MENZEL and ELAINE D. SMOLKO

Downloaded by SUFFOLK UNIV on January 19, 2018 | http://pubs.acs.org Publication Date: January 13, 1984 | doi: 10.1021/bk-1984-0239.ch003

Departments of Pharmacology and Medicine and Comprehensive Cancer Center, Duke University Medical Center, Durham, NC 27710

Animal experimentation produces most available data for chemical toxicity. Methods for using this data in assessing human risk are presented, with emphasis on mathematical modeling. Any interspecies extrapolation effort must account for variations in morphology and metabolism. Provided a general similarity exists, the specific differences do not preclude analysis. Application of a mathematical model using anatomical, rather than pharmacokinetic, compartments for determination of toxicity of chemicals is discussed. The Miller Model is presented as a method for quantitative assessment of tissue dose of toxicant following inhalation. Metabolism is discussed in terms of reactive intermediates and of species and strain variations. These approaches indicate progress in the use of animal toxicology data for predicting human risk. Chemical t h r e a t s t o human h e a l t h d i c t a t e a c a r e f u l a p p r a i s a l o f new chemicals. A continued r e a p p r a i s a l o f known t o x i c a n t s i s a l s o needed t o ensure that the human h e a l t h r i s k s are balanced by b e n e f i t s from the use of these compounds. The t o x i c i t y o f chemicals i s l a r g e l y determined by animal experimentation. The r i s k t o man i s estimated by i n t e r s p e c i e s e x t r a p o l a t i o n from animals t o man. The basis f o r animal experimentation i s the presumed s i m i l a r i t y between animals and man. T h i s assumption i s so commonplace that i t has become a truism. Yet, the s p e c i f i c d i f f e r e n c e s between man and animals become more apparent as quantitative and p r e c i s e measurements o f t o x i c i t y become increasingly available. Are animals good surrogates f o r humans? Do animal experiments present an accurate p i c t u r e o f the hazards t o man o f chemical exposures? Can animal experiments be

0097-6156/84/0239-0023S06.00/0 © 1984 American Chemical Society

Rodricks and Tardiff; Assessment and Management of Chemical Risks ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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ASSESSMENT A N D M A N A G E M E N T OF CHEMICAL. RISKS


used to p r e d i c t q u a n t i t a t i v e l y the outcome i n man? Do l i f e t i m e exposures of animals present an analogy with human l i f e t i m e exposures? These are but a few of the questions r a i s e d d a i l y i n the c o n c e p t u a l i z a t i o n of animal experiments and use of r e s u l t a n t data i n s o c i e t a l d e c i s i o n s . In a c e r t a i n sense, these are p h i l o s o p h i c a l questions; but i n another sense they are h i g h l y p r a c t i c a l , and s o l u t i o n s are urgently needed. We w i l l d i s c u s s some recent approaches to these questions. Our remarks w i l l be r e s t r i c t e d to chemicals and to i n t e r s p e c i e s extrapolation. The aim of t h i s d i s c u s s i o n i s to provide a framework f o r i n c r e a s i n g the p r e c i s i o n of experiments using animals as surrogates f o r man. I n t e r s p e c i e s D i f f e r e n c e s i n Morphology The morphology of animals i s so apparently d i f f e r e n t from that of man that i t i s o f t e n overlooked i n the i n t e r p r e t a t i o n of t e s t r e s u l t s or i n the s e l e c t i o n of appropriate species f o r t e s t i n g . Comparative anatomical studies have revealed important s i m i l a r i t i e s as w e l l as d i s s i m i l a r i t i e s . Inhalation toxicology experiments, for example, are particularly sensitive to anatomical d i f f e r e n c e s . Q u a n t i t a t i v e morphometric s t u d i e s o f the human and animal lung were begun by Weibel , who used a specialized statistical method to sample the highly heterogeneous s t r u c t u r e of the normal lung. These s t u d i e s and those of Kliment (2) l e d to an anatomical model which, d e s c r i b e s the equally b i f u r c a t i n g nature of the human lung. Figure 1 i s a schematic r e p r e s e n t a t i o n of these r e l a t i o n s h i p s between the tube diameter and length, and the number of b i f u r c a t i o n s . Each b i f u r c a t i o n i s r e f e r r e d to as a generation. The number of generations i n animal lungs d i f f e r s from that i n human lungs, mainly because of the smaller s i z e of animal lungs compared to those of adult humans. Also, rodent lungs d i f f e r i n the generation at which a l v e o l i begin to appear branching o f f from the main bronchi or breathing tubes. The a l v e o l i represent the gas-exchange r e g i o n s of the lung and are important s i t e s of uptake of i n h a l e d t o x i c a n t s . D e t a i l e d morphometric analyses of r a t , guinea p i g , and r a b b i t lungs have been reported. Studies of mouse lungs are now i n progress. These data, combined with c o n t i n u i n g s t u d i e s of the human lung, w i l l provide a "map" of the lung showing i t s dimensions with r e l a t i o n to the number of generations. As discussed below, such a map can be described mathematically and used i n a model of the r e g i o n a l d e p o s i t i o n of gases and p a r t i c l e s i n the lung. While human and animal lungs are d i s s i m i l a r i n s i z e and number of generations, they are s t r i k i n g l y s i m i l a r i n t h e i r manner of o r g a n i z a t i o n . V a r i a t i o n s i n d e t a i l s have been noted and measured, i n c l u d i n g such f e a t u r e s as angles between b i f u r c a t i o n s , s i z e , and thickness of tube and a l v e o l a r w a l l . These d i s t i n c t i o n s are, however, amenable to a n a l y s i s and



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Interspecies Extrapolation

Figure 1. Schematic r e p r e s e n t a t i o n between tube diameter and length b i f u r c a t i o n s i n the human lung.

of r e l a t i o n s h i p s and number of


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ASSESSMENT A N D M A N A G E M E N T OF C H E M I C A L RISKS

e x t r a p o l a t i o n through p h y s i c a l p r i n c i p l e s of gas flow and aerodynamics of p a r t i c l e s i n gases. D i f f e r e n c e s between human and animal lungs can be turned to advantage once q u a n t i t a t e d , provided a general s i m i l a r i t y e x i s t s . The d e p o s i t i o n of gases and p a r t i c l e s i n the nasopharyngeal r e g i o n of the r e s p i r a t o r y t r a c t i s l i k e l y to be of i n d u s t r i a l importance, since the work place i s o f t e n contaminated with relatively large p a r t i c l e s l i k e l y to be deposited i n the nasopharynx and not i n the lung. Recently, i n h a l a t i o n s t u d i e s of formaldehyde spurred comparative studies of the nasopharyngeal region of the r e s p i r a t o r y t r a c t . Mice and r a t s developed nasal tumors when exposed to l e v e l s of formaldehyde near those o c c u r r i n g i n the work place. S i m i l a r tumors have been reported i n workers exposed to formaldehyde vapors. Workers i n n i c k e l r e f i n e r i e s have an increased incidence of nasal tumors, presumably because of the d e p o s i t i o n of n i c k e l a e r o s o l s i n the nasopharynx. Schreider and Raabe (3_) examined three species o f animals by producing s i l i c o n rubber c a s t s o f the nasopharynx. These casts of dogs, r a b b i t s , and monkeys r e v e a l e d a h i g h l y complex, convoluted pathway l e a d i n g t o the lungs. Sections through these casts were made, and the area as a f u n c t i o n of the distance from the e x t e r i o r to the i n t e r i o r was compiled. By combining the measured areas with the a i r flow through the nose, the Reynold's number can be computed t o indicate the turbulence of the a i r flowing through the nasopharynx during breathing. Such c a l c u l a t i o n s lend themselves to p r e d i c t i o n s of the d e p o s i t i o n of aerosols w i t h i n given r e g i o n s of the nose. The naospharyngeal removal of gases can be measured d i r e c t l y (4.), but these measurements are d i f f i c u l t to make and are n e c e s s a r i l y r e s t r i c t e d t o a few values of flow. An anatomical d e s c r i p t i o n i n mathematical terms, on the other hand, allows a more general approach. Gas uptake can be modeled i n terms o f the p h y s i c a l p r o p e r t i e s of the gas and the gas uptake i n p h y s i o l o g i c a l f l u i d s , as described below f o r the lung. The d i v e r s i t y i n the nasopharynx of rodents and man makes rodents l e s s u s e f u l f o r s t u d i e s o f t o x i c i t y of l a r g e p a r t i c l e s or t o x i c a n t s r e a d i l y removed by s o l u t i o n . Rodents are r e q u i r e d to breathe through t h e i r noses. Major d i f f e r e n c e s . i n dose and dose-rate are l i k e l y , then, between man and rodents f o r compounds deposited predominantly i n the nasopharynx. The r a t , but not the hamster, mouse, r a b b i t , and guinea pig, has mucous glands as does man. Lamb and Reid used the r a t to produce experimental b r o n c h i t i s from i n h a l a t i o n of s u l f u r dioxide and c i g a r e t t e smoke (5.-1). I t i s questionable i f other animal species would have responded s i m i l a r l y , because of the anatomical d i f f e r e n c e s .


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General Mathematical Models i n Toxicology Considerable progress has been made i n a p p l y i n g pharmacokinetic modeling t o animal data and e x t r a p o l a t i o n t o man. These models s e i z e upon the s i m i l a r i t i e s and d i s s i m i l a r i t i e s between s p e c i e s . Himmel s t e i n and Lutz (_8) suggest that models built on "physiological pharmacokinetic principles can confidently p r e d i c t e f f e c t s i n man. These models use basic p h y s i o l o g i c a l and biochemical i n f o r m a t i o n t o develop d i f f e r e n t i a l equations d e s c r i b i n g drug or toxicant d i s t r i b u t i o n and d e p o s i t i o n . These models are c h a r a c t e r i z e d by anatomical (organ volumes and t i s s u e s i z e s ) , p h y s i o l o g i c a l (blood flow rate and enzymic r e a c t i o n rates), thermodynamic (binding isotherms), and t r a n s p o r t (membrane permeability) considerations. A rational mathematical model a l s o a i d s i n the d i r e c t i o n o f research and testing o f hypotheses which are sometimes difficult or impossible to t e s t d i r e c t l y . As an example of the a p p l i c a t i o n o f t h i s methodology. Dedrick and h i s a s s o c i a t e s examined the pharmacokinetics o f the cancer Chemotherapeutic drug, methotrexate (8^12). This physiological scale-up pharmacokinetics focuses on i n t e r s p e c i e s d i f f e r e n c e s i n s i z e and p e r f u s i o n c h a r a c t e r i s t i c s of anatomical compartments rather than pharmacokinetic compartments. The p h y s i o l o g i c a l parameters and the s e t of d i f f e r e n t i a l equations that allow such p r e d i c t i o n o f plasma and t i s s u e concentrations i n man based on the data obtained i n animals, at a given l e v e l and frequency of exposure, have been reported. T h i s approach has been used s u c c e s s f u l l y t o adjust the dose of methotrexate used c l i n i c a l l y to avoid undesired t o x i c side e f f e c t s from the drug.


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n

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A p p l i c a t i o n o f Mathematical Models t o I n h a l a t i o n Toxicology Because the lung i s composed o f over 40 d i f f e r e n t c e l l types which are r e g i o n a l l y concentrated, knowledge of the r e g i o n a l dose of a toxicant t o the lung i s very important. Inhaled gases may a f f e c t only, the upper, middle, or lower r e s p i r a t o r y t r a c t . The symptoms r e s u l t i n g from such r e g i o n a l d i s t r i b u t i o n are q u i t e distinct. For example, sulfur dioxide exposure results predominantly i n c h r o n i c b r o n c h i t i s i n r a t s ( 5 ) , while chronic exposure to ozone or n i t r o g e n dioxide leads predominantly t o emphysema (13). Chronic b r o n c h i t i s i s r e s t r i c t e d t o the upper airways, s t i m u l a t i n g the production o f mucus and o b s t r u c t i o n o f the major airways; emphysema i s r e s t r i c t e d t o the r e s p i r a t o r y region of the lung and decreases gas exchange by decompartmentalization o f the a l v e o l a r r e g i o n o f the lower respiratory tract. At present, d i r e c t measurement of the r e g i o n a l dose of an i n h a l e d t o x i c a n t i s d i f f i c u l t , i f not impossible. An a l t e r n a t e approach i s t o combine the anatomical


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models of the lung with the p h y s i c a l p r o p e r t i e s of the i n h a l e d gas and i t s chemical r e a c t i v i t y with c e l l u l a r c o n s t i t u e n t s and products to p r e d i c t which regions of the lung are most l i k e l y to r e c e i v e the greatest dose; that i s , to provide a s p e c i a l i z e d model based mostly on anatomical f e a t u r e s of the lung r e l e v a n t t o r e g i o n a l uptake of t o x i c a n t . Using the bifurcating model of the human lung and morphometric data on guinea p i g and r a b b i t lungs, M i l l e r , et a l . (4) demonstrated the s i m i l a r i t y between animals and man in r e g i o n a l pulmonary d e p o s i t i o n of ozone ( O 3 ) . The transport and removal of Oo i n the lung was simulated by using a binary c o n v e c t i v e - d i f f u s i o n equation:

3Ç + D

3C = ( D

x

3t

3x

m o l

+ D ) ed

Q2Ç 3r

+ 1 3C + ^ C ) 2

r 3r

3x

+ S

2

where C, U and S represent species-averaged population concentrations, v e l o c i t y , and source terms, r e s p e c t i v e l y , i n a given airway at a s p e c i f i e d l o c a t i o n and time. The a x i a l and r a d i a l d i r e c t i o n s are χ and r ; t equals time; D ^ i s the molecular d i f f u s i o n c o e f f i c i e n t of O3; and D represents the d i f f u s i o n c o e f f i c i e n t due to eddy d i s p e r s i o n . This equation represents a statement that the removal of O3 by the lung i s a f u n c t i o n of convection, a x i a l and r a d i a l d i f f u s i o n , and chemical reactions. Chemical r e a c t i o n s are assumed to occur instantaneously. Compared to the mechanics of breathing, the chemical r a t e s of r e a c t i o n of Oo with c e l l u l a r c o n s t i t u e n t s and exudates are so fast as to De instantaneous. Thus, O3 and the cellular c o n s t i t u e n t s or exudates (mucus, i n most cases) can not c o e x i s t i n the same s o l u t i o n . The l i q u i d phase can be thought of as c o n s i s t i n g of two l a y e r s ( Ijj). The t i s s u e dose, then, can be c a l c u l a t e d from the case where the O3 c o n c e n t r a t i o n i n the o v e r l y i n g l a y e r exceeds the concentration of the r e a c t a n t s secreted by the c e l l . In most p a r t s of the lung, c e l l s are covered with a mucus l a y e r ; from the chemical composition of the mucus and the stoichiometry of r e a c t i o n of Oo with these c o n s t i t u e n t s , the dose of O3 reaching the underlying c e l l s can be c a l c u l a t e d knowing the i n h a l e d O3 concentration. In F i g . 2 , taken from M i l l e r , et a l . (4)» the t i s s u e dose of O3 i s p l o t t e d against the r e g i o n of the lung for several inhaled O3 concentrations. Remarkably s i m i l a r p l o t s were obtained f o r r a b b i t and guinea p i g lungs. Even more important, the r e g i o n of the lung r e c e i v i n g the l a r g e s t p r e d i c t e d dose of O3 i s that which shows the greatest anatomical damage i n a c t u a l exposures of animals (15»1j6). This r e g i o n of the r e s p i r a t o r y bronchiole and the a l v e o l u s was thought to be e x t r a o r d i n a r i l y s e n s i t i v e to x

mo

e d




MENZEL AND SMOLKO

Figure 2 . Tissue dose of O3 p l o t t e d against the r e g i o n of the human lung f o r s e v e r a l Inhaled O3 concentrations.


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O3, but these data suggest that the apparent anomalous s e n s i t i v i t y i s r e a l l y due to a d i f f e r e n c e i n dose-rate. When combined with measurements of the removal of Oo from the nasopharyngeal cavity, quantitative estimates of the i n t e g r a t e d t i s s u e dose can be made. These estimates suggest that r a b b i t s r e c e i v e about twice the t i s s u e dose of man f o r the same i n h a l e d O3 c o n c e n t r a t i o n . While r e g i o n a l s i m i l a r i t i e s exist f o r man and these two animal species, q u a n t i t a t i v e d i s s i m i l a r i t i e s are present. A study now i n progress extends t h i s approach to r a t s and mice, which have a v a i l a b l e a much l a r g e r compilation on the h e a l t h e f f e c t s of O3. The s c a l i n g of these h e a l t h e f f e c t s t o man at ambient concentrations of O3 i s a l s o underway.

Polymorphic Xeno^ou? ççroçyga ttetafroliaB i n Anlialn *nfl Man Current thought holds that most t o x i c organic compounds and carcinogens are non-toxic or non-carcinogenic i n t h e i r o r i g i n a l form and must be metabolized to a more r e a c t i v e metabolite or ultimate t o x i c a n t (17). This idea of " r e a c t i v e i n t e r m e d i a t e s " has been one of the most u s e f u l concepts i n e x p l a i n i n g t o x i c i t y of a number of compounds and has advanced considerably our understanding of the chemistry of t o x i c i t y and c a r c i n o g e n i c i t y . Most compounds which are converted t o more t o x i c r e a c t i v e intermediates are s u b s t r a t e s f o r the mixed f u n c t i o n oxidases (MFO), which are dependent on cytochrome P-450 (P-450) isoenzymes f o r a c t i v i t y . Depending upon the species and organ, as many as seven P-450 isoenzymes have been reported. P-450 isoenzymes are under g e n e t i c c o n t r o l i n both man and animals. Using the a n t i h y p e r t e n s i v e drug debrisoquine, Smith and h i s colleagues have s t u d i e d the g e n e t i c v a r i a t i o n s of s e v e r a l human populations and s e v e r a l s p e c i e s of rodents and s t r a i n s of r a t s . Debrisoquine i s metabolized almost e x c l u s i v e l y to 4-hydroxy debrisoquine (18). 4-Hydroxy debrisoquine and i t s parent compound are e a s i l y detected i n the urine by gas chromatography. Urine i s c o l l e c t e d f o r 8 hrs f o l l o w i n g the o r a l a d m i n i s t r a t i o n of a s i n g l e 10 mg dose of the drug. The r a t i o between drug and metabolite excreted i n the urine ranges from 0.01 to 200. In man, the phenotype corresponding t o extensive metabolizers (EM) ranged from 0.01 to 9t while poor metabolizers (PM) ranged from 20 to 200 (18). In a survey o f 258 u n r e l a t e d white B r i t i s h subjects, 8.9? were found to be the PM phenotype. The EM phenotype was dominant, and the degree of dominance was estimated at 30?. From s t u d i e s of nine pedigrees, the PM phenotype was found t o be an autosomal Mendelian r e c e s s i v e characteristic. These s t u d i e s confirm and extend the previous estimates of PM occurrence of 6? i n whites (19) 7? i n blacks, and 1? i n Egyptians (20). PM excrete only 1-3? of the drug and a t t a i n much higher blood l e v e l s than EM. f



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Other drugs whose metabolism by man i s under the same g e n e t i c c o n t r o l as debrisoquine are guanoxon and phenacetin (21 ), phenytoin (22), metiamide (22) and 4-methoxyamphetamine (24). Antipyrine metabolism i s , however, not under the same c o n t r o l as debrisoquine metabolism, despite the s i m i l a r i t i e s o f metabolism of these two drugs by the MFO system (25). Diversity in oxidative drug metabolism has been demonstrated f o r 4-hydroxy amphetamine f o r the guinea p i g and r a t (24). The human EM phenotype excretes 4-hydroxyamphetamine p r i m a r i l y as the .Q-demethylated product, with minor amounts o f parent drug, H - o x i d a t i o n or b - o x i d a t i o n products. The human PM phenotype excretes l e s s o v e r a l l drug; a l a r g e f r a c t i o n i s unchanged drug and N-oxidation product, with only small amounts of .Q-demethylated drug. Guinea pigs excrete the O-demethylated product exclusively and i n l a r g e amounts. Rats excrete p r i m a r i l y the ΰ-demethylated product, with some parent drug and N-oxidation product. Thus, the r a t and guinea p i g represent the human EM, but not the PM, phenotype. Polymorphism i n debrisoquine metabolism was demonstrated f o r the r a t (26). Seven s t r a i n s of r a t s were examined f o r t h e i r a b i l i t y t o metabolize debrisoquine. The Lewis s t r a i n was an EM, while the DA s t r a i n was a PM. Aside from the 4-hydroxy metabolite, r a t s a l s o excreted 6-hydroxy debrisoquine. The DA s t r a i n excreted l e s s o f both metabolites. The Lewis and DA s t r a i n s showed good recovery of the drug i n 24 hr u r i n e s with 74.6 and 56$ of the dose excreted, r e s p e c t i v e l y . Phenacetin was used t o t e s t f u r t h e r the polymorphic nature of drug metabolism i n these two s t r a i n s , since the O-demethylation o f phenacetin i s under the c o n t r o l of the same gene l o c u s as debrisoquine i n man (£1). Considerably l e s s paracetamol was excreted by DA r a t s (38?) than by Lewis r a t s (54?). DA r a t s a l s o had e l e v a t e d l e v e l s of 2-hydroxy drug, a pathway a s s o c i a t e d with hemotoxicity i n man ( 2 7 ) . S p e i l b e r g (28) r e c e n t l y reviewed the importance of g e n e t i c c o n t r o l of drug metabolism i n chemical t e r a t o g e n e s i s . Phelan, et a l . (29) reported discordant expression o f f e t a l hydantoin syndrome i n heteropaternal d i z y g o t i c human twins. They suggest that the d i f f e r e n c e i n response t o hydantoin t e r a t o g e n e s i s i n man i s due to d i f f e r e n c e s i n i n h e r i t e d a b i l i t y t o metabolize drugs. S p e i l b e r g c i t e s experimental evidence i n mice i n support of t h i s hypothesis. The A£l l o c u s i n mice, which enables i n d u c t i o n o f arylhydrocarbon hydroxylase, was manipulated by Shum, et a l . (30) t o demonstrate greater t e r a t o g e n i c r i s k i n those f e t u s e s possessing the Ah+ phenotype. Speilberg also points out the importance of the mother's phenotype i n determining the blood c o n c e n t r a t i o n o f the teratogen and, t h e r e f o r e , the t r a n s p o r t of the chemical across the placenta t o the f e t u s . In S p e i l b e r g ' s opinion, the u n c e r t a i n t y i n current t e s t s i s too great t o be of much help i n p a t i e n t counseling a f t e r drug or t o x i c a n t exposure. The a l t e r n a t i v e i s a drug



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nihilism, as the result of physician uncertainty regarding animal tests. Avoiding a l l drugs during pregnancy, except Aû extremes seems a drastic response. Studies of the effect of polymorphism i n drug metabolism on teratogenic tests appears to us to be urgently needed. Comparisons of metabolism between different strains of rabbits, beyond the present selection of strains for thalidomide s e n s i t i v i t y , are needed. Species variations i n the ϋ-methylation of pyridine have been reported by D'Souza, et a l . (3D* Cats, gerbils, guinea pigs, and hamsters are EM, while humans, mice, rabbits, and rats are PM (Table I ) . The mouse, rabbit, and r a t are, thus, good surrogates for man for amines. Since methylation to quaternary amines could represent an intoxication step, experiments with EM would be more conservative. A l l of these studies point to the need for a greater precision i n examining drug metabolism i n animals, with regard not only to the species chosen, but also to the strain chosen. Strains mimicking one or more human phenotype should be included i n each compound evaluation.


r

Table I .

Species Variations i n N-Methylation of Pyridine

Species

Total Excreted

Exténue Methvlators Cat Gerbil Guinea Pig Hamster

% Dose Excreted i n 24 hrs. N-Methylpyrridinium Excreted

75 52 66 67

40 26 30 26

67 66 51 48

9 12 19 5

Poor

MettiYlator? Man Mouse Rabbit Rat

conclusion

Animals continue to be f a i r surrogates for man, despite marked differences. Anatomical variations are important, since they can a l t e r the quantitative response of test animals. The upper



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r e s p i r a t o r y t r a c t i s p a r t i c u l a r l y r e l e v a n t i n t h i s regard f o r i n h a l a t i o n exposures of animals. P a r t i c l e s i n h a l e d by man may be excluded from the lower r e s p i r a t o r y t r a c t of rodents, because of the smaller diameter of the airway and the greater f i l t r a t i o n of p a r t i c l e s i n the nasopharyngeal c a v i t y . While the lower r e s p i r a t o r y t r a c t s of rodents and man a l s o d i f f e r , q u a n t i t a t i v e morphometric s t u d i e s have improved maps of t h i s area to the point at which they are u s e f u l i n mathematical modeling. Using the physiological-anatomical approach to k i n e t i c modeling, accurate p r e d i c t i o n s can be made f o r drug t o x i c i t y i n man based on animal s t u d i e s . Hopefully, the i n h a l a t i o n modeling of a e r o s o l s and gases w i l l be v a l i d a t e d s h o r t l y and w i l l add t h i s dimension to p r e d i c t i o n of human t o x i c i t y from exposure to these t o x i c atmospheres. Polymorphism in oxidative metabolism by man adds significant complexity to drug and toxicant testing. If o x i d a t i v e metabolism of x e n o b i o t i c compounds continues t o be considered a major determinant i n t o x i c i t y , c a r c i n o g e n i c i t y , and t e r a t o g e n i c i t y , then animal surrogates w i l l have to be chosen with the c h a r a c t e r i s t i c s of drug metabolism i n mind. The l a c k of o x i d a t i v e metabolism i n man i s a s s o c i a t e d with adverse drug r e a c t i o n s due to higher blood l e v e l s o f drugs; e.g. g r e a t e r apparent potency. The l a c k of such metabolism i n animals results i n false negative e r r o r s f o r t e s t s i n which the metabolite i s the ultimate toxicant; e.g. selectivity in t e r a t o g e n i c i t y i n rodents. Polymorphism i n drug metabolism i s presumably due to g e n e t i c c o n t r o l over the i n d u c t i o n and type of P-450 isoenzyme present i n the t i s s u e s . Not only are fewer metabolites formed by PM, but the products are d i f f e r e n t . Some minor m e t a b o l i t e s may be more t o x i c than the major ones. The matter i s complex and not amenable to i n t u i t i v e a n a l y s i s . One could argue that r a p i d metabolism leads t o r a p i d e l i m i n a t i o n , but r a p i d metabolism could l e a d t o higher l o c a l concentrations of reactive metabolites and toxicity by overcoming d e t o x i f i c a t i o n pathways. Slower metabolism could l e a d t o l a r g e r amounts of unreacted drug and, t h e r e f o r e , to longer exposure to both parent drug and i t s metabolites. I f the parent compound i s a drug or t o x i c a n t i n i t s own r i g h t , PM leads t o greater toxicity. PM could a l s o l e a d to longer exposure to low l e v e l s of r e a c t i v e metabolite, which i n t u r n could l e a d t o greater toxicity. A quantitative analysis using k i n e t i c modeling appeals t o us as a s o l u t i o n t o t h i s dilemma. Obviously, much greater comparative d e t a i l i s needed t o assure the continued u s e f u l n e s s of animal surrogates i n p r e d i c t i n g human t o x i c i t y .


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Literature Cited 1. Weibel, E. R. Morphometry of the Human Lung. Academic Press: New York, 1963, 151 pp. 2. Klimet, V. Folia Morphol. 1973, 21, 59. 3. Schreider, J. P.; Raabe, O. G. Anat. Rec. 1981, 200, 195. 4. Miller, F. J.; Menzel, D. B.; Coffin, D. L. Environ. Res. 1978, 17, 84. 5. Lamb, D.; Reid L. J. Pathol. Bacteriol. 1968, 96, 97. 6. Reid, L. Arch. Intern. Med. 1970, 126, 428. 7. Reid, L. M.; Jones, R. Environ. Health Persp. 1980, 35, 113. 8. Himmelstein, Κ. J.; Lutz, R. J. J. Pharmacol. Biopharmac. 1979, 7, 127. 9. Lutz, R. J.; Dedrick, R. L.; Matthews, Η. B.; Eling, T. E.; Anderson, M. W. Drug Metabol. Disp. 1977, 5, 386. 10. Lutz, R. J.; Dedrick, R. L.; Zaharko, D. S. Pharmac. Ther. 1980, 11, 559. 11. Bischoff, Κ. B.; Dedrick, R. L.; Zaharko, D. S.; Longstreth, J. A. J. Pharm. Sci. 1971, 60, 1128. 12. Bischoff. Κ. B. Cancer Chemother. Reports. Part 1. 1975, 59, 777. 13. Freeman, G.; Juhos, L. T.; Furiosi, N. J.; Mussenden, R.; Stephens, R. J.; Evans, M. J. Arch. Environ. Health. 1974, 29, 203. 14. Astarita, G. Mass Transfer with Chemical Reaction; Elsevier: New York, 1967, p. 53. 15. Stephens, R. J.; Sloan, M. F.; Evans, M. J.; Freeman, G. Amer. J. Pathol. 1973,74,31. 16. Stephens, R. J.; Sloan, M. F.; Evans, M. J.; Freeman, G. Exp. Mol. Pathol. 1974, 20, 11. 17. Miller, J. Α.; Miller. E. C. in Origins of Human Cancer; Hiatt, Η. H.; Watson, J. D.; Winsten, J. A. Eds: Cold Spring Harbor Laboratory: Cold Spring Harbor, New York, 1977, p. 605. 18. Price-Evans, D. Α.; Mahgoub, Α.; Sloan, T. P.; Idle, J. R.; Smith, R. L. J. Med. Genet. 1980, 17, 102. 19. Mahgoub, Α.; Idle, J. R.; Dring, L. G.; Lancaster. R.; Smith, R. L. Lancet 1977, 2, 584. 20. Mahgoub, Α.; Idle, J. R.; Smith, R. L. Xenobiotica 1979, 9, 51. 21. Sloan, T. P.; Mahgoub, Α.; Lancaster, R.; Idle, J. R.; Smith, R. L. Br. Med. J. 1978, 2, 655. 22. Idle, J. R.; Sloan, T. P.; Smith, R. L.; Wakile, L. A. Br. J. Pharmacol. 1979, 66, 430. 23. Idle, J. R.; Ritchie, J. C.; Smith, R. L. Br. J. Pharmacol. 1979,66,432. 24. Kitchen, I.; Tremblay, J.; Andre, J.; Dring, L. G.; Idle, J. R.; Smith, R. L.; Williams, R. T. Xenobiotica 1979, 9, 397.


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25. Danhof, M.; Idle, J. R.; Teunissen, M. W. E.; Sloan, T. P.; Breimer, D. D.; Smith, R. L. Pharmacology 1981, 22, 349. 26. Al-Dabbagh, S. G.; Idle, J. R.; Smith, R. L. J. Pharm. Pharmacol. 1981, 33 161. 27. Ritchie, J. C.; Sloan, T. P.; Idle, J. R.; Smith, R. L. Ciba Foundation Symposium 1980, 76, pp. 219. 28. Speilberg, S. P. NEJM 1982, 307, 115. 29. Phelan, M. C.; Pellock, J. M.; Nance, W. E. NEJM 1982, 307, 99. 30. Shum, S.; Jensen, N. M.; Nebert, D. W. Teratology 1979, 20, 365. 31. D'Souza, J . ; Caldwell. J.; Smith, R. L. Xenobiotica 1980, 10, 151. RECEIVED

November 4, 1983


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Interspecies Extrapolation - ACS Symposium Series (ACS Publications)

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