FACTORS INFLUENCING THE DOSE FOR GASES, VAPORS Yves Alarie, Ph.D Professor Emeritus U niversity of Pittsburgh,USA

A.HIGH WATER SOLUBILITY AND HIGH REACTIVITY For these gases, SO 2, HCl, HF, HCHO, calculate like aerosol, assume 100% for α. Essentially completely removed by solution and reaction at the surfaces of the respiratory tract and very efficiently scrubbed by the upper respiratory tract. Very little penetration to the alveolar region until high concentrations are reached and the scrubbing capability of the upper respiratory tract becomes overwhelmed.

Several gases have been investigated for regional penetration, SO 2, several aldehydes. (1) High water solubility alone is not sufficient since acetone or ethanol (2,3) are not entirely removed by the nose while SO 2 is. With SO 2 the reaction with water at pH 7.4 will yield SO 2 + H 2 O —> H 2 SO 3 – > H + + HSO 3 - HSO 3 - —> H + + SO 3 = Then reaction of HSO 3 - and SO 3 = with protein disulfide bonds to yield sulfonates. Similar schemes can be presented for several water soluble and reactive chemicals. In essence, a “sink” is present to retain these types of gases or vapors.

a)Importance in toxicological studies Since mice, rats, guinea pigs, hamsters are obligatory nose breathers, the first area affected by these gases will be the nose. Nasal carcinoma in rats and mice vs. monkeys and humans due to formaldehyde is a good example.

b)Extrapolation from small laboratory animals to humans Toxicological studies of these gases will always underestimate their pulmonary toxicity for humans, assuming that the species in question has the same sensitivity as humans. This is somewhat compensated by the fact that for a given exposure concentration the rodents will receive a higher net dose due to their higher minute ventilation to body weight ratio. However, again deposition sites may differ. A very difficult problem.

c)Evaluation of toxicological effects The nose is a complex organ and several sections must be made in order to evaluate the effects at different levels. It is difficult to predict where lesions will occur but three major epithelial types must be examined: squamous epithelium, respiratory epithelium and olfactory epithelium as shown in the next figure. Buckley et al. (1) have presented a detailed analysis of lesions in the nasal passages for 10 different chemicals. Very few inhalation toxicology studies included histopathological examination of the nose prior to 1980.

B.LOW WATER SOLUBILITY AND HIGH REACTIVITY These will penetrate deeper into the lung, NO 2, O 3, COCl 2, TDI, methyl isocyanate (MIC), react with pulmonary tissues, generally produce edema. They are sometimes called true pulmonary irritants. Calculate like aerosol, assume 100% for α. Only a few gases have been investigated, 24,25,26.

For example 14 CMIC appeared in arterial blood within minutes from the beginning of exposure. This was measured as 14 C, not 14 CMIC. However, 14 CMIC was found to be covalently bound to hemoglobin within the red blood cell. How did it get there? It is possible that MIC could have been transported within the red cells conjugated to a small peptide and released as MIC there to react with hemoglobin, since if reacted with an SH group of something like glutathione or cysteine, this reaction is reversible.

C.LOW REACTIVITY WITH SURFACE OF RESPIRATORY SYSTEM Assume inert gas and no metabolism. The following physical and physiological parameters will influence their uptake and clearance in the body. a)Physical Parameters i) Concentration in Air, as Partial Pressure Concentration in air (mm Hg) determines maximum concentration (mm Hg) in blood since equilibrium between the two compartments (i.e., inspired air and blood) will be established at some time. Once equilibrium is established no more can be taken into blood.

b)Physiological Parameters i) Minute Ventilation Important for high S substances. In essence, so much chemical is needed to be transferred into blood to reach equilibrium with inspired air, that bringing more by increasing ventilation will increase the rate at which equilibrium will be reached. ii) Cardiac Output Important for low S substances. In essence, so little chemical is needed to be transferred into blood that exposing blood faster to alveolar air will decrease the time needed to reach equilibrium with inspired air.

D.PRACTICAL USE OF THE CONCEPTS IN TOXICOLOGY Alveolar air Since alveolar air (not inspired air) 27 is always at equilibrium with capillary blood a sample of this air must be obtained (see next page). 27Inspired air will reach equilibrium with alveolar air at one point but alveolar air is always as equilibrium with capillary blood as discussed in previous pages.

Alcohol breath test 28 To determine the blood concentration from a sample of alveolar air: Alveolar Air  S = Blood Concentration The alcohol breath test is of obvious forensic importance. Many articles have been written since the article of Haggard et al 28. See some recent articles and the proposed value of 1756 for S 29,30.

Monitoring of solvent concentration in blood of exposed workers. Measurement of alveolar air concentration has been made for many solvents. It is a way to measure exposure and is used for establishing a Biological Exposure Index (BEI) by the ACGIH. An example is given in Table 13.Table 13.

Is a vapor biotransformed and if so at what rate? The principles given above can be used as follows: i) In a closed chamber, the concentration of an inert gas or vapor will decrease due to absorption in blood and tissues of the animal or human subject located in the chamber and then will remain stable as equilibrium between inspired air and blood is reached. ii) If a substance is biotransformed equilibrium will not be reached, reduction of the concentration will continue. iii) The rate of disappearance of the gas or vapor, after the equilibrium phase, is at the rate at which the gas or vapor is metabolized.

Laboratory Animals Vs. Humans. It is important to remember that small laboratory animals have a higher ventilation to body weight ratio than humans. Therefore if a mouse and a human are exposed at the same concentration, equilibrium will be reached faster in the mouse than the human. This was used with a canary or mouse in mines, to monitor carbon monoxide. When the canary falls off its perch due to high COHb the human still has time to escape. I would not try this, but in any event it illustrates the principle.

The second item to remember is that small laboratory animals have a higher metabolic rate than humans. Thus if a metabolite of the gas or vapor is the active toxic species more of it will be produced than in humans even though both are exposed to the same concentration. Here PB-PK and other modeling techniques are very useful. 31,32,33,34