-lournci of Hczurdou» Materials,:!:! 119891 26~-2l'l:!Elsevier Science I'ublishers B.\'" Amsterdam - Printed in The ~I'I herlands

THE TOXICITY OF A RED PHOSPHORUS SMOKE AFTERREPEATED INHALATION

T.C. MAHrtS. H.F. cxn ,( ;){AVE .. J.A.G. EDGINTON. P. H)(.'E and N.L. CI-l.OSS

('VE Parton 0,,[111. Salisbury. Wiits" England SP41i·/(t ((in'at Britain)

(Hecpiw·d -Ianuarv 19, 19r;9; accepted April 11. 19891

Summary

;ovlir!'and rats were exposed 1.01 he smoke produced by ignit.ion of a red phosphorus pyrotechniccomposition, 1 hid. r,d/week, at. two different dOR<' 11'\'t'I~, IO~l'th(!r with controls. ThE:' mice re-ceived 180 exposures, while the rats received 200 exposures, Guinea ri~~also underwent 200l'X'posures HI.the !",\'pr (',,!'(,I'n! rat ion.hut .. 11animal" 1."1",,\·d "t I lu- hi~!lll't' (,nc('111rnu .n died duringur immediatelv nftt-r tilt' first dose. Grov.1:h ofthe test groups of mice and rats was depressed during'!',t' p'\pr"!lrt' PI'TII'(1. Of1(UIl specific toxicity appeared not to he present in rats and was genernllvconfined TO (he respiratory tract of the mice and the guinea pigs. A sign ificantly higher proportionof tht: test group mouse lungs showed aggregates of macruphages containing granules than waspresent in the (;'JI1Lrol !!wup. Severe congestion was observed in practically all the lungs from thedecedent high-dose ).,'TliUp ~i!lea pigs.

Introduction

Obscurant white smokes have a variety of civilian and military uses, Severaltypes are available including those generated from zinc oxide/hexachloro-ethane mix!UTE''' [l-:{ J, titanium dioxide/ hexachloroethane mixtures [4] andcinnarnic add {i).1i I.Zinc oxide/hexachloroethane smokes have been shown toproduce histological changes in the lungs of animals, including pulmonary oed-ema, alveolitis and fibrosis [2--1.7J. Furthermore, there have been numerouscage report.s of lung damage being produced by zinc oxide/hexachloroethanesmoke in humans !8-15]. An alternative to zinc smokes, with, however, dif-ferent military uses, is the ignition of phosphorus compositions: red phospho-rus burns to phosphorus pent oxide and, when ignited in conditions of normalhumidity, gives rise to a strongly hygroscopic aerosol consisting largely of or-t hophosphoric acid [16].

The acute inhalation toxicity of a red phosphorus smoke was studied byBallantyne [1'1], The l-h LC,;owas 271 (196-670) for the mouse, 1217 (970-1489) for the rat, 61 (52-80) for guinea pigs and 1689 (1200-3586) for rabbits(mg/ m3, with 95'C confidence limits), Lary nzeal and tracheal necrosis and

\~! J9HH Elsevier Science Publishers B.Y.

270

acute inflammatory changes were seen in the decedents. In another study [18]rats and rabbits were exposed to single sublethal doses of one of two differentred phosphorus smokes: rabbits killed at 24 h showed acute inflammation ofthe larynx and trachea and, in some cases, necrosis. Alveolitis was also seen,About half of those killed at 14 d showed laryngeal and tracheal inflammation,and all had some degree of alveolitis. Changes seen in the rats were similar andpulmonary congestion was also observed, The response to the two smokes,produced from the pyrotechnic compositions was similar. Despite t.hese find-ings in the respiratory tracts of experimental animals, the use of red phospho-rus smokes does not seem to have produced case reports of serious humanpoisoning, Nevertheless, as part of a continuing programme of study into thehealth effects of military smokes, we have investigated the repeated dose tox-icity of a smoke produced from a red phosphorus pyrotechnic mixture,

Method

AnimalsThree hundred 23-d old Porton-strain female mice, of mean weight 16,0 g,

150 41-d old Porton Wistar-derived female rats, of mean weight 113 g, and 13841-d old Dunkin-Hartley female guinea pigs, of mean weight 350 g, were sup-plied by the Animal Breeding Unit, CDE Porton Down, The animals wererandomly allocated into groups of approximately equal sizes, designated con-troIs, low and high. This resulted in groups of 100 for the mice and 50 for therats, The size of the dose groups of guinea pigs was 48 in the case of the controland low dose group, while there were 42 high dose group guinea pigs. Groupsof animals were then subdivided. In the case of the mice, subdivision was intogroups of ten to a cage, whilst the rats were divided into subgroups of five: theguinea pigs were similarly subdivided and housed as groups of six. Special pre-cautions were not taken to prevent huddling, despite the possibility that thismight reduce the inhaled dose. This was because a limited study suggests thathuddling does not to affect the inhaled dose of toxicant, at least in the case ofrats [19]. Between exposures, the animals were housed in special accomoda-tion near to the inhalation unit, and then, after the last exposure, transferredto permanent accommodation.

Generation of the smokeThe pyrotechnic mixture was supplied by Dispersion Division, CDE. This

mixture (Table 1) was in the form of granules. A measured amount of thematerial, the quantity depending on the desired concentration, was ignitedwith a fusee match in a static 10m3 chamber, To assist combustion a jet of airwas blown over the burning pyrotechnic mixture,

::'71

TABLE J

{.~(llnpl)sitiun of the pyrotechnic mixt ure

Amorphous oiled red phosphorus yr,':;1)()I~'\'in~'1butyral BLJll :,":i

ExposureThe animals were exposed to the freshly generated smoke, 1 hid, 5d/week.

until, in the case of the mice. they had experienced 180 exposures. Animalsfrom the other two species underwent 200 exposures (i.e. 40 weeks; Table 2),except for the high-dose group of guinea pigs. all of which died during theexposure period. The high dose was one that was considered to be likely toproduce definite toxicity in mice. but which, on a single dose basis, would belikely to he sublethal. The lower dose was intended to 1)(' about 1/8 of the highdose. Corresponding groups of each species were exposed together. startingwith exposure of the controls to air within the chamber and ending wit h ex-posure of the high dose group, Because the concent.rat ion of smoke fell duringexposure, t he pyrotechnic mixture, in the form of fresh granules. was ignitedto maintain the desired concentration. During the half-hour interval betweenexposure (If the various dose groups, the chamber was thoroughly cleaned ofdetritis: at the end of the high dose exposure, the chamber was well-washedtwice,

The smoke was sampled by drawing air at 5 l/min through GF/B filter pa-pers. Filter papers were eluted into 40 ml of 1.25 N sulphuric acid. After filtra-tion. a 4-ml aliquot was added to [) ml 0.25% ammonium molybdate and 1 mlO,06r:Ihydrazine sulphate, This was mixed well, heated at 80 C for 20 min andCtlolpdd IHi made up to 10 ml wit h 1.:2.'1.\ sulphuric acid. The optical density ofhe resultant solution was read against a standard curve made using solutions

of potassium dihydrogen phosphate in 1.25 S sulphuric acid. Eight samples of5 min duration and 9 sarnp le-sof;W s duration were t a ke n in the low and highdose exposures respectively. The impacted mass (If smoke IVa", weighed, allow-ing calculation of the concern ration of solid material during exposure. Resultswer« expressed as mg/rn' phosphorus. The particle size of the smoke was notdetermined.

During the exposure period animals were examined for abnormal behaviouror ill-health, They were weighed weekly during exposure, and the mean \I, holebody weight of each dose group of animals, relat ive to the mean weight of the,·"m..-sponding controls W11,. reg-ressed against rime. Animals showing clinicalsigns suggestive of ill-health were killed using sodium pentobarbital: those aliveat the end of the study (19 month" aft er the start of exposure) were similarlykilled, Animals killed or found dead \»ere examined post-mortem, At autopsy,lungs, larynx, trachea, liver, kidneys, spleen, thymus, mammary glands, sali-

r

272

TABLE 2

Concentration of smoke exposures, total dose received and duration and number of exposuresduring the study

Species Dose-group Jl:o.of I<;xposures Duration Number ofanimals h exposures

Conca Dosemg m ":' rng min m-3

Mice Control 1(1{) 0 0 1 180

Ll)w 100 16.2:: 4.a 175,222 1 18U

High 100 12S..:;=29.S 1,308.080 1 180

Rats Control 5U 0 0 t 200,Low 50 16.6.::9.8 199,504 1 2UO

High 50 !:?7,:;::::'R.ii 1.530,274 1 200Guinea- Control 48 0 (l 1 200Pigs Low 48 16.6:::9,8 199,405 1 200

High 42 127,5 ± :{S.5 b , b

"± S.D, Ias phosphorus I."No guinea pig survived to the end of the exposure period in this group. Consequently the meanconcentration represents the mean had they survived to 200 exposures,

vary glands and adrenals and thyroids, ovaries, heart, pancreas, oesophagus,stomach, small and large intestine were taken. Inmice mesenteric lymph nodeswere taken in addition to the above organs, while cervical lymph nodes wereexamined in the rats and guinea pigs. In rats, but not in the other two species,the pituitary gland, brain, uterus and a portion of skin were also examinedmicroscopically. In the case of the high dose group guinea pigs, only the lungswere examined. Any other organ showing any macroscopical abnormality wasalso processed. After fixation in neutral buffered formalin, sections 5:!:2 µmthick were cut and stained with haematoxylin and eosin. Histological data wererecorded and analysed using a PLACES data acquisition system (Apoloco Ltd.,90 King Street, Newcastle-under-Lyme, England, ST5 1JB, uxi. This pack-age was run on a Micro VAX II minicomputer (Digital Equipment Corpora-tion, Maynard, !\'1A,U,S.A.).

StatisticsThe number of decedents were insufficient for statistical analysis of histo-

logical data. Amongst the survivors, the frequency of histological changes inanimals from the test groups was compared to that in the corresponding con-trol groups, using Fisher's exact test, The mean weight of the test groups di-vided by the mean weight of the corresponding control group was regressedagainst time, The significance of the linear relationship was estimated fromthe ratio of the variances attributable to the regression compared to the resid-ual (F-test).

Results

ExposureThe exposure concentrations were close to the anticipated concentrations

of 15 and 180 mg/rn".

SurvivalThe study was remarkable for the high decedency in many groups (Table 3),

Thus, in t he case on the mice, more than 50% died in each dose group duringthe study. However, in this species, a smaller number of controls died than inthe low-dose group (59% versus 63%). On the other hand there appeared to bea clear excess of deaths in the high-dose group, in which about 80% died, Amongthe rats, death rats were similar in the three dose groups, while in the guineapigs, 15% and 38% died before the end of the experiment in the control andlow-dose group respectively. All guinea pigs in the high-dose group died duringor immediately after the first exposure.

GrowthThe weight of the low-dose group mice, relative to the controls, decreased

during exposure, especially over the first 40 days (P <0.05). A greater, moreconsistent and more significant fall was seen in the high-dose group micet hroughout 1 he exposure period (P <0,001 ). The relative weights of both testgroups of rats fell throughout the exposure period. at a somewhat higher ratein the case of the high-dose group animals t han in the low-dose group IFig, 1),In the case of both groups, statistically significant relationships were revea led(P <0.001), The relative weight of the low-dose group of guinea pigs rose dur-ing exposure.

TABLE:!

Numbers of animals dying before completion of the study

Species T()tal dying Total numberof animals

During During in groupstudy exposure

59 2~ 1006:~ 21 10078 4:; 10013 1 ;')0

12 2 5010 1 ijO7 :J 48

18 10 4842 ·12 42

Mice ControlLowHigh

Rat~ ControlLowHigh

Guinea- Cotllru)

Pigs LowHigh

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Fig. :, Mean weight of test groups of rats relative to the controls during exposure.

Early deathsTwenty control mice, 7 of which died during exposure had microscopic ap-

pearances consistent with severe chronic murine pneumonia. A further twohad a milder form of the same condition. In some animals aggregations of mac-rophages were seen in the alveoli or bronchioles. Alveologenic carcinoma wasnot seen in the lungs from decedents of this group, One (thymic) lymphomawas seen in an animal dying during the observation period, as well as a uterinesarcoma in another mouse. Several animals showed salivary gland abscesses.Among the lowdose group decedents, histopathological appearances were gen-erally similar. Thirty out of 63 animals had severe chronic murine pneumonia,with a similar proportion being affected in those dying during exposure andthose dying during subsequent observation. A further 3 had a milder form ofthe same changes. In many of the animals aggregates of macrophages were seenin the alveoli and/or bronchioles. One alveologenic carcinoma was seen in ananimal dying during the observation period. Four lymphomas were seen, noneinvolving the thymus. In two cases lymphomatous infiltration was seen onlyin the lymph nodes, while in another the liver was additionally affected. Thefourth lymphoma involved lymph nodes, liver and spleen, Although there were

many decedents in the high dose group. histological appearances were similarto the other groups, Severe chronic murine pneumonia was observed in 36 outof 78 mice, while three had the less severe form of the same changes. As in theother groups, macrophage aggregat.ions were often seen in the alveoli or bron-chioles, Neither alveologenic carcinoma nor lymphoma was seen in the highdose group decedents,

Among the decedent rats, these was only one animal. a rat with pyelone-phritis, that died during the exposure period in the control group, Those con-trols dying during the observation period had lungs free from significant his-tological abnormalities, However, in this group, there was a single case of focalhepatic necrosis and two of focal portal fibrosis. Twelve animals showed evi-dence of rat nephropathy. while 4 fibroadenomas of the mammary glands wereseen, Furthermore. there was an adrenal cortical adenoma and a pituitary ad-enoma. Histological changes in the low-dose group animals were similar: twodie-d during the exposure period. with focal portal fibrosis and acute pyelone-phrit i-, respert ivelv. One animal dying during the observation period had em-phvserna, while ~{hod evidence of lymphomatous infiltration in the lung andt hI' Iiver. In one inst ance this infiltrat inn was add it ionally present in the kid-IW~ ~ rind adrenal ghmd: in another, lymphomatous infiltration was also pres-e nt in the spleen. HOI nephropathy wac; common as in the controls, but only(Inc' fibroadenoma and one fibroma of the mammary gland was seen. In thehigh do"e group. \ er) mild pulmonary oedema was observed in 0 -.ingle animal('1\ ing during exposure, while foam cells were present in the lungs of another,Two decedents showed portal fibrusi-, one exhibited acute J!~dflnt'phritis anda fibroadenoma of the mammary gland was seen, Additionally there was onesquamous cell carcinoma of the skin and -1 pituitary adenomas,

Lymphoid foci were frequent in decedent guinea pigs of all groups. Intersti-t ial nephritis was also common. Among t he control animals, one showed ag-~n>l!atb of macrophage" in the lungs. while another had focal necrosis of theliver. In the low-dose group. pulmonary oedema was seen in two guinea pigsdying during the exposure period and It lung abscess in a third, Bile duct hy-perplasia, an abscess in the ahdominal cavity and a uterine fibroid were eachseen on single occasions in animals dying during the observation period, Atautopsy of the high-dose group guinea pig'-, which all died ill t he first day ofthe study (see above), only the lungs were taken for histological processingand study. Macroscopically, there was haemorrhage and collapse, while mic-roscopically there was severe congestion with in some instances mild to mod-erate oedema.

SurvivorsHistological changes observed in mice t hat survived to the end of the exper-

iment are shown in Tables 4-6. Abnormalities were not seen in the mammaryglands. pancreas. thyroid, oesophagus, duodenum, jejunum, ileum and colon,

276

TABLE 4

Selected histological changes seen in mouse surv ivors after exposure to t he smoke

Organ and histological change Dose woup

Control(41 )"

Low(~!7,)

LungAlveologenic carcinomaAlveolar aggregates of macrophages with granulesBronchiolar aggregates of macrophages wit h l,'1'anulesInterstitial pneumonitisBronchiectasisPerivascular lymphocytic infiltrationPeribronchial lymphocytic infiltration

LarynxEpithelial lymphocytic infiltrationIntraluminal pus

TracheaEpirhelial lymphocvtic infiltration

L) mph nodes f mesenteric)Lymphoma

ThymusLymphoma

HeartFocal merit is

LiverPerivascular lymphocytic infiltrationPeriportal lymphocytic infiltrationHepatomaHepatocellular carcinoma

SpleenLymphoid hyperplasra

Kidne ....sLymphocytic infiltrationChronic interst it ial nephritis

AdrenalsLymphocytic infiltration

2')

1

1033

291

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2027

25

18

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Non-Protocol organs,

o

Cerrical Iymph nodeslymphoma o (l

"Group size.b P<O.O;;: significal1tly more frequent in test WOllp than controls,'P<O.OOl: significantly more frequent in test l{TOUp than controls.d P<O,05: significantly less frequent in test group than controls.

TABLE;;

., .... r"!'_ ..

Organ and histological change

Selected histulngical changes seen in rat survivors after exposure iu the smoke

l.unuAI\'"uliti~Peribwl1chioiar lymphocyt.ir infiltrat ionPerivascular lvmphocyt it- infiltrat iOI1

OedemaEmphysema

LarynxSubmucosul lymphocyt ic infiltration

TraclieoSuhmucosal lymphocyt.ir infiltration

.\!cmrr.G,,) GiandsLipomaFibroadenomaDud ectasia

ThyroidCystic changes

LiverNodular hyperplasiaFocal periportal fibrosis

PancreasArterit is

."Ip/ppnMegakaryocytopoesis

KidneysXephropathyIntcrst it inl lyrnphocyt ic irrfilt.eat ionXephrocakinosls

AdrrnalNoduleMedullary haemorrhage

PituitaryAdenoma

Fteru sAdenumatous polvp

Dose group

Control Low(:li)a (:~H).

.: 5roo) ~7~)-

16 170 0o 2

High(40 J.

2

o

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0 ()

~5 5

., 4

:l1~ 14

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(I 2

:!~ 20"19 8"8 6

(I 26 7

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8

(j

o2

ooo

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o.:an roup size."Signilicantly less frequent than controls (P<O.051.

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TABLE 6

Selected histological changes seen in guinea !Jig survivors ufter exposure to the smoke

Organ and histological change

LungPeribronchiolar lymphocyt ic infiltrat i')11Perivascular lymphocytic infiltrationPleural thickeningAlveolar macrophagesCongestionBronchopneumoniaAbscess

Mammary elandLipoma

HeartScarring 1!t'GU i

LeerFocal necrosisBilinry hyperplasiaPatchy !ibrf_J~is

PancreasIslet ceil adenoma

Kiene»Chronic intersi itial nf"phriTi~:\ephrocalcinos.i"

0::01";'-Se!'~-cs cys:

------------------- , .._- -- ---_ .._,---_._-------

(;a:i bicddcrCn(Jlt'cy,:;ti:i~ n

'Group s ize.b~i;:r.ifkant!~· n;:'.rt' :rt'ql:fr.t in lest ar imal- I i'<II.tI;,).

while all stomachs examined. except for one from a high-dose animal, werenormal. The exception showed ulceration. In the salivary glands, one instanceof lymphocytic infiltration and of a cyst could be seen, both in animals fromthe control group. Lymphomas were seen only in the low-dose group, wherethere were three. All were of thymic origin and additionally involved the cerv-icallymph nodes, In one case the mesenteric nodes that were examined werealso affected,

There were no dose-related changes in the rat lungs: in all groups of rats, ahigh proportion had pulmonary collapse and congestion. Two animals. fromthe high-dose group, had intra-alveolar oedema, Most extra-respiratory organs

279

were normal, including the heart, lymph nodes, salivary glands, urinary blad-der, skin, oesophagus, stomach, duodenum, jejunum, ileum and colon, and brain.All ovaries were normal except for one from a control animal with a seriouscyst,

Since no high-dose group animal survived the study, histological changesobserved in guinea pig tissues were only analyzed statistically in case of thecontrols and low-dose group, The prevalence of histological changes in the twogroups was similar in both respiratory and extra-respiratory organs, A possibleexception was the frequency of chronic interstitial nephritis, which was sig-nificantly more common in the low dose group (P<O,05). Among the inciden-tal findings, lymphoid nodules were seen in the lungs oft-he survivors, as in thedecedents. No hist opat hological abnormality was observed in the trachea, lar-ynx, salivary or adrenal glands or in the thyroid, thymus, spleen or gut (oeso-phagus, stomach, duodenum, jejunum, ileum, colon). Among the non-protocolorgans, two control gall bladders were abnormal, one with acute cholecystitisand one with chronic cholecystitis, Two control urinary bladders had squa-mous metaplasia, One from the control group and one from t he low-dose grouphad chronic inflammatory changes.

Discussion

There was a marked species difference in tolerance to the smoke; rats weremost resistant, guinea pigs least and mice occupied an intermediate position,Similar species differences have been observed in previous studies, althoughthe death rate in the high-dose guinea pigs, in the present study, was excep-tiona! r 3,6, J 9 :Z:Z J. The concentrations used here represent, in mice, less thannile half and 1/17 of the single dose LC' .(1 reported by Ballantyne r 171 for thehigh and low dose groups. In the ruts 1he concentrations used in the presentexperiment were equal to 1/10 and 1/7;:' of the LC:;[,. On the other hand Bal-lantyne [17 J reported a single doee LC"o in guinea pi~", which \\,u,. less thanhalf the high concentration used in the present study. The favourable survivalfigures observed in rats and the high mortality in the high-dose group of guineapigs is thus readily explicable, Thus the use of a high dose that was, as intended.(oxic (0 mice but also sublethal, produced death in guinea pigs and hardly af-fected the fill ".This was, of course, Ihe consequence of using the same exposureconcentrations in the three species, The survival figures in the present studyare rather more difficult to compare with the sublethal study in rats [18],because in t hat study t he duration of exposure was only 30 min. In that studya Ioral of 5 out of 30 rats, exposed to two different concentrations of red phos-phorus smokes, died.

Except in the case of the guinea pigs, growth was reduced in all the testanimals, Moreover, it was not possible to demonstrate a no-effect-dose for

depression of growth, Furthermore, the smoke affect.ed survival in the miceand the guinea pigs. By contrast, rat survival was unaffected,

With the exception of the high-dose group guinea pigs, decedents mostlyfailed to show pathological changes, either in the respiratory tract. or elsewhere,likely to have been a consequence of exposure to the test material. On the otherhand the high-dose guinea pigs, all of whom died during or just after the firstexposure, showed pulmonary congestion accompanied, in some cases, by hae-morrhage and collapse, all of which were undoubtedly responses t.othe smoke,In all species the scanty changes seen in survivors mostly appeared to be inci-dental. An exception was the observation of aggregations of macrophages foundin lungs of the test groups of mice, These have been described in previousrepeated dose studies in which military smokes were tested [3], and may, inpart, be caused by secondary infection, Histological changes relat-ed to the testmaterial were not seen in the rats or surviving guinea pigs and t he absence ofsuch signs may have been due to the long observation period,

Incidental findings of interest, in the present study, included renal diseasein all three species: chronic interstitial nephritis was seen in the mice andguinea pigs and nephropathy in the rats [23-26]. A number of alveologeniccarcinomas was observed in mice, but this finding was not frequent and therewas no indication of a dose response in the prevalence of the tumour in thedifferent groups: no attempt was made to separate these neoplasms into benignand malignant as is sometimes done r27], and the criteria for histopathologicaldiagnosis were those of Stewart et al, [28,29]. The presence of lymphoid nod-ules, seen in the lungs of both decedent and surviving guinea pigs, is well-recognised as a frequent incidental finding of unknown origin, in this species[30,31J,

Despite the fact that red phosphorus smoke is largely an aerosol of ortho-phosphoric acid, which has a pKa of about 2, for its first proton [32], specificdamage to the respiratory tract has only rarely been seen in the present study,If. at the end of exposure, damage was present, it had been reversed by the endof t.he observation period. This suggests that delayed and incompletely revers-ible changes, similar to those seen in animal studies of the toxicity of zincoxide/hexachloroethane smoke, are unlikely to occur with phosphorus smokes,Assuming that the experimental animal data correlate with human experi-ences, with both smokes, the latter is much less likely to give rise to long termrespiratory impairment than the former, On the other hand, the very markedspecies differences in lethality, observed in the present study, must indicatecaution in quantitative extrapolation to humans of the study data, reinforcedas they are by major differences in acute lethality figures (17), Thus therewould be considerable difficulties in producing exposure limits for the use ofthe smoke. from present. and past lethality data [17,18]. Whilst it is reasonableto assume that the guinea pig death rate is due to the peculiar sensitivity ofthat species to irritant aerosols [33], no similar explanation can be supplied

for the discrepancy between the lethality observed in the mouse and rat, norare there data on which to base a choice of the most suitable species for ex-trapolation to man, A threshold limit value-time weighted average (TWA) of1mg/rn ' and a short term exposure limit (STEL) of3 mg/m3has been adoptedfor phosphoric acid by the American Conference of Governmental IndustrialHygienists [34 J, The TWA, which is, of course, for an 8 h exposure, is difficultt.ocompare with the present study. since it is designed for pure phosphoric acid,By contrast the smoke used in the present study is likely to contain manycompounds in addition to orthophosphoric acid [16}, Such compounds mightinclude cyclotetraphosphoric and other polyphosphoric acids, as well as smallamounts of phosphine, produced from phosphorus trioxide,

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:--H I l!-lH'i 1 :;0$-:109.

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.-1 t

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21

22

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