Halogenated hydrocarbon environmental pollution: The special case of halogenated anesthetics

ENVIRONMENTAL

RESEARCH

28, 212-239

(1982)

Halogenated Hydrocarbon Environmental Pollution: Special Case of Halogenated Anesthetics

The

J. R. MARIER Environmental

Secretariat,

Division of Canada,

of Biological Ottawa KIA

Received

January

Sciences, National OR6, Canada

Research

Council

26, 1981

INTRODUCTION

For several years, there has been concern about the adverse environmental consequences accruing from the use of chlorinated hydrocarbon compounds, although information regarding effects on humans has been relatively sparse (see reference to NRC-Canada). However, there are several similarities between chlorinated hydrocarbon pollutants (e.g., DDT or PCBs, etc.) and modern-day halogenated hydrocarbon anesthetics; the similarities include their respective chemical structure, their bioaccumulation in adipose tissue, and their dependence on the liver for metabolic transformation and partial excretion. Moreover, several halogenated hydrocarbon anesthetics have been in widespread clinical use during the past three-or-so decades, and this has led to a substantial accumulation of knowledge bearing on the toxicological cause/effect aspects in humans. Aside from the likelihood that the various halogenated hydrocarbon compounds in the human environment may have similar metabolic effects, there is also the very real possibility that diverse exposures to a variety of these compounds might lead to “cross-sensitization” phenomena among susceptible humans. STRUCTURAL

AND

METABOLIC

CONSIDERATIONS

The toxicity aspects of halogenated hydrocarbon anesthetics have been reviewed by several authors during the past decade, and a selected list of such reviews is presented in Table 1. Originally, the modern-day anesthetics were formulated in an attempt to provide greater convenience (i.e., less volatility and/or flammability) along with greater metabolic stability to thereby achieve more effective anesthesia per unit of anesthetic agent. At the outset, these compounds were thought to be “inert” and metabolically unreactive; this impression was a consequence of extensive pretesting in various animal species. In this regard, Cohen and VanDyke (1977) cited a 1965 study by Litchfield, who noted that over 50% of the toxic effects subsequently seen in humans had been missed in the animals, whereas 20% of the (animal-based) predictions for human toxicosis turned out to be incorrect. During recent years, several “surprises” have occurred, and this has given rise to controversy. Conn (1974) has provided an illuminating comment about the nature of this controversy: 212 0013-9351/82/030212-28$02.00/O Copyright All rights

Q 1982 by Academic Press, Inc. of reproduction in any form reserved.

HALOGENATED

HYDROCARBONS

TABLE REVIEWS

1

DEALING WITH THE OF HALOGENATED HYDROCARBON

213

TOXIC

ASPECTS

ANESTHETICS

Authors

Year

Cascorbi Cohen and VanDyke Conn Dykes et al. Gottlieb and Trey Holaday Holaday and Fiserova-Bergerova Jee et al. Joshi and Conn Loew et al. Mazze and Cousins Mazze et al. Rehder and Sessler Samuelson et a/. VanDyke Vaughan et al.

1973 1977 1974 1972 1974 1977 1979 1980 1974 1974 1973 1977 1974 1976 1979

In every field, there is at least one issue which inexplicably and spontaneously stimulates intense and emotional controversy. During this Symposium, the subject of hepatotoxicity, for example, has so far been discussed quietly, rationally, and intellectually. Whenever the word Halothane has been mentioned, however, a trace of stridency creeps into the voices of the discussants. While I agree with nearly all of the facts presented by the opposing parties to support their viewpoints, I do not necessarily agree with the conclusions that have been drawn. It is therefore my purpose to examine the available data and, as rationally and dispassionately as possible, to determine what valid conclusions can be reached. . . . Part of the controversy is caused by the failure of the protagonists to listen to one another. More disturbing is the fact that they do not want to listen to each other.

Note that the word “Halothane” was used in the preceding quotation. It is therefore appropriate, at this point, to refer to Table 2, which shows that several of the modern-day anesthetics are also known by a different name. This recourse to an “alias” should not be overlooked, especially if only one of the names appears on any future suspect list. Essentially, the twin goals sought in modem-day anesthetics-decreased volTABLE DUAL

NAMES

MODERN-DAY

Anesthetic Enflurane Fluroxene Halothane Isoflurane Methoxyflurane

2

USED TO IDENTIFY ANESTHETICS

Also known as Ethrane Fluomar Fluothane Forane Penthrane

214

J. R. MARIER

atility with increased metabolic stability and effectiveness-were achieved by introducing halogen atoms (primarily fluorine) into the hydrocarbon structure (Cohen and VanDyke, 1977). Figure 1 illustrates the compositional makeup of several anesthetics, in comparison with chloroform and trichloroethylene. Note that there are structural differences: (i) Halothane contains a bromine atom. (ii) Fluroxene, which was the first fluorinated anesthetic to see clinical use, contains no chlorine or bromine atom; it is relevant to point out that, in contrast to the other fluorinated anesthetics, fluroxene is flammable (Cohen and VanDyke, 1977). (iii) Whereas the fluorine atoms of fluroxene and halothane are bound exclusively as CF, groups, this is not the case for enflurane, isoflurane, methoxyflurane , or sevoflurane . Although it is generally true that the metabolic stability of an anesthetic will increase as a direct function of its fluorine content (Holaday and FiserovaBergerova, 1979), its anesthetic potency depends on its solubility in fatty tissue (Cohen and VanDyke, 1977). The fluorine contents of the six anesthetics shown in Fig. 1 are approximately (molar precentage basis): Methoxyflurane Halothane Fluroxene Enflurane Isoflurane Sevoflurane

23 29 45 52 52 66

In Fig. 2, note that methoxyflurane is readily absorbed into fat tissue, but is prone to metabolic breakdown (Fig. 2a); however, the high solubility of

“J-T-J, I I F F

Cl-C-Cl Cl chloralmn

EllHWl”e

F Cl I I F-C-C-H

FlWOX~fl~

Cl F I I H-C-C-O-C-H

,-T-p,-:-, I I F H lSOR”,S”~

A Lx, Hdothane

!li A M~thOX~fl”,P”~

F F--c-F

H

H-C-O-C-F F-C-F

H B

%ORWP”e

Cl \

c-c<

”

x Cl Trirhloroclhylcn.

FIG. 1. Structure of six modern-day anesthetics, in comparison with trichloroethylene. Reprinted, with permission, from Cohen and VanDyke (1977).

chloroform

and

HALOGENATED

Methoxyflurone

507

;;

.w’

Trichl0roethylens.r.“‘. . ...’ ... ,./ ,..” ,:. ,..’ ,:’ ‘.’ aChloroform (..’ ,S’Halothane

40.

E si 2 ii

. ....”

215

HYDROCARBONS

3c-

2. .’ )“Isofl”rane-enfturane 2 w ::Fl”roxsns is? :* f 10-; Diethyl ether i Cyclopropane 0

(a)

200

400

FAT/GAS

Go0

PARTITION

I Boo loo0 COEFFICIENT

(b)

OIL/GAS

WRTITION

COEFFICIENT

1ooo 5000 (37 C)

FIG. 2. (a) Increasing metabolic instability of anesthetics as a direct function of their solubility in fat tissue. Reprinted with permission; from Feingold and Holaday (1977). (b) How the effectiveness of an anesthetic improves as a direct function of its solubility in fat tissue. Reprinted with permission; from Cohen and VanDyke (1977).

methoxyflurane in fat tissue correlates with its high degree of potency as an anesthetic agent (Fig. 2b). Perhaps the latter consideration accounts for the widespread clinical use of methoxyflurane, and a similar reason could be proposed to explain the popularity of halothane. And yet, it is the metabolic instability of such compounds that has given rise to the controversy. It appears likely that one of the factors that contributed to the controversy was the relatively long time lag that elapsed before clinical symptoms were recognized in some of the postanesthesia patients (see Table 3). Meanwhile, epidemiological studies had begun to indicate potential long-term risks to operating-room personnel exposed to what has been termed an occupational “anesthetic pollution” problem (Dahlgren, 1979; Halsey, 1978); this aspect will be discussed later in this report. Table 4 presents data relating to the uptake of various anesthetics by man during the course of conventional anesthesia. On the basis of the data shown in Table 4, it can be calculated that the total uptake of a given anesthetic averages 9.3 + 1.8 g per hour of anesthesia. It can also be seen that, whereas 95% of the isoflurane is exhaled in unaltered form, only 1% of the methoxyflurane is readily expelled. TABLE 3 TIMELAGBETWEENTHEINTRODUCTIONOFSEVERALANESTHET~CSINTOCLINICALPRACTICE,AND SUBSEQUENTRECOGNITIONOF METABOLICPROBLEMS IN SOMEPOSTANESTHESIAPATIENTS Anesthetic

Year introduced

Fluroxene Halothane Methoxyflurane

1953 1956 1960

Year when problem recognized 1972 1964 1966

Nature of the metabolic problem

Reference

Hepatotoxicity Hepatotoxicity Nephrotoxicity

Fiserova-Bergerova, 1977 Sherlock, 1978 Hagood et al., 1973

216

J. R.

MARIER

TABLE 4 FATE OF INHALATION ANESTHETKS IN MAN Percentage of absorbed dose

Anesthetic

Average dose exposure, (min)

Average dose absorbed, w

Exhaled unchanged

Identifiable metabolites

Isoflurane Enflurane Fluroxene Halothane Methoxyflurane

130 115 142 75 138

18.1 18.4 32.0 9.2 18.1

95 83 58 46 19

0.2 2.4 10.0 25.0 44.0

Source.

Unaccounted for 4.8 14.6 32.0 29.0 37.0

Adapted from Holaday (1977).

Furthermore, about one-third of the fluroxene, halothane, or methoxyflurane is “unaccounted for” via urinary excretion. Presumably, the preponderance of this unrecovered fraction is retained in adipose tissue, as illustrated in Table 5. Note that, as the duration of anesthesia increases from 1 to 6 hr, the halothane concentration in fat increases 9%fold, whereas the increase is only twofold in liver. Thus, after 2 hr of anesthesia the concentration of halothane in fat is 11 times higher than that in liver. This has serious implications for obese persons, as will be discussed later in this report. Cohen and VanDyke (1977) have described the sequence of events involved in the metabolic breakdown of modern-day anesthetics. Usually, drug metabolites are less active biologically than the parent compound, and this has been termed a “detoxification” process; however, the converse is true for anesthetics, because toxic manifestations are a direct function of their metabolic instability. Primarily, the breakdown of halogenated anesthetics is mediated by means of microsomal enzymes in lipid-rich membranes such as those in the endoplasmic reticulum of the liver (see Fig. 3), especially as the liver has the highest level of enzymic activity. The breakdown pathway can be either oxidative or reductive, and both require NADPH (nicotinamide adenine dinucleotide phosphate); also, both involve glucose-to-glycogen phosphorylation. In such a case, oxidation is synonymous with hydroxylation. Halogenated hydrocarbon anesthetics can undergo TABLE 5 RETENTION OF HALOTHANE (mg/lOO g) IN BLOOD AND SEVERAL LENGTHSOF TIMEOFANESTHESIA

SOFT TISSUES,

AFTER DIFFERENT

Duration of anesthesia (hr) Tissue

0.5

1.0

1.5

2.0

2.5

3.0

4.5

6.0

Blood Fat Brain Liver

15.1 55 20 17

16.9 100 25 22

18.0 130 20 18

16.8 250 31 23

21.0 300 31 26

22.0 450 33 35

18.5 650 38 43

21.5 950 45 48

Source. Adapted from Duncan and Raventos (1959).

HALOGENATED

217

HYDROCARBONS

Mitochondrionmooth endoplasmic reticulum asmic reticulum Plasma membrane

atin e Cell

wali

FIG. 3. Diagram of a typical cell, showing endoplasmic reticulum. Reprinted, with permission, from Watson (1976)

two types of oxidation, i.e., dehalogenation or 0-dealkylation (ether cleavage). The next step in the process is thought to involve conjugation of a metabolite, i.e., either to a protein or to a phospholipid. Anesthetic metabolism utilizes the cytochrome P-450 hemoprotein system found exclusively in cellular endoplasmic reticulum. [Note: Cytochrome P-450 has also been described as “an oxygen-activating terminal oxidase of mixed-function oxidase system in hepatic microsomes” (Takahashi et al., 1977)]. The metabolic breakdown of halogenated hydrocarbon anesthetics activates this system. Whenever synthesis exceeds destruction (and, consequently, whenever the amount of enzyme exceeds what is normally found), so-called “enzyme induction” has taken place, thus leading to enzymatic cleavage of the parent compound and liberation of reactive metabolites. As would be expected, the oxidative and reductive pathways utilize this microsomal system in different ways; this is shown in Fig. 4 which illustrates the metabolic breakdown of halothane along with possible conjugation of the various metabolites. Figure 5 presents an alternate sequence for halothane metabolism, whereas Figs. 6 to 9 illustrate the metabolic-breakdown pathways for methoxyflurane, fluroxene, enflurane, and isoflurane, respectively. Here, it is important to emphasize that any chemical (e.g., phenobarbital) that induces the activation of liver microsomal enzymes can potentiate the breakdown of halogenated hydrocarbon anesthetics (Cohen and VanDyke, 1977) and that patients exposed to a combination of such compounds will be at greater risk (Poppers, 1980). Table 6 presents a summary of the metabolites identified (i.e., in Figs. 4 to 9) as a consequence of metabolic breakdown of various anesthetics. There are several distinctions worthy of note: (i) As would be expected, Halothane is the only one of these anesthetics that releases Br. (ii) Only under reductive (i.e., anoxic) conditions does halothtne release significant amounts of F. (iii) Of these anesthetics, fluroxene is the only one that does not release F. Therefore (as will be shown), it is not surprising that several researchers have used Br release to monitor halothane breakdown, whereas F release has been used to

218

J. R. MARIER

. Halothane metabolism by reductive or oxidative pathways, showing the various interthat may be formed. Reprinted, with permission, from Reynolds and Moslen (1977).

monitor the breakdown of methoxyflurane, enflurane, and isoflurane. As regards fluroxene, Mathieu et al. (1975) have suggested that trifluoroacetate be measured for breakdown-monitoring purposes. And as for monitoring Cl release, Cascorbi (1973) has commented that, “Chloride occurs abundantly in nature, and short of employing a specifically-labelled chlorine, it would be impossible to trace its origin.” The preceding statement applies particularly to routine clinical monitoring. protein t

CF,CClBrH

/

CF,COOH

/ rp \ “St,.

Mrrrapruric derivative +

(cF,&IB~ 1 Bound to phospholipid

acid

/ (CF,=CCIB~ + Fi Bound to phorpholipid

FIG. 5. Halothane metabolism. Reprinted, with permission, from Cohen and VanDyke (1977).

Cl I ti-C-G

PATHWAY

F I -OCHJ

I

“1 Cl

0

F +

F

H-0-!-L-O-CH3+2HCL

[CH20]

:

I HOH

I Cl 0 H-A

0 - OEALKYLATION

9

!-OH

3

+ 2HF

ICI

-c

SJ

7

(+2HF)

\ OH

HO

6. Methoxyflurane

FIG.

Probable

metabotism. Reprinted, with permission, from Loew et nl, (1974). Inhibitors

enzymes

co2 f CF3CH2-O-

CH = CH,

FklroV3ne

P450

system

I

CF,CH,OH

Carbon

tetrochloride

to Glucuronide f

Trifluoroethonol Carbon tetrochloride Pyrazole Aminotriozole

Microsomol ethanol oxidizing system [MEOS] Alcohol dehydrogenose [ADH] Cotolose I CF,COH Trifluoroocetoldehyde

Disulfirom

Acetoldehydeoxidose CF,COOH Trifluoroacetic FIG.

acid

7. Fluroxene metabolism. Reprinted, with permission, from Cascorbi (1973). 219

J. R. MARIER

220

“,’ : “-f-;-OH]

+

: :

[CF20]

I

HOH

o- DEALKYLATION

J

I ~-+Hl

H-~-c-oH+2HF

(+.HCL+HFl

C Ho

/

+

[U4F20]

C \‘*2wF) OH

FIG. 8. Enflurane metabolism. Reprinted, with permission, from Loew er al. (1974).

Sofar in this presentation, the modern-day halogenated anesthetics have been discussed in terms of their formulation, nomenclature, chemical structure, anesthetic potency, metabolic uptake, distribution, retention, and breakdown, along with identification of known metabolites.

: “I PATHWAY1

:

‘-~-~-“-~-”

PATHWAY

E

TFA.

F F-k-C-OH

p

0)

; TFA.

FIG. 9. Isoflurane metabolism. Reprinted, with permission, from Loew et al. (1974).

HALOGENATED

TABLE METABOLITES

IDENTIFIED

Anesthetic Halothane

Oxidative Reductive

Methoxyflurane Fluroxene

6

AS A CONSEQUENCE OF METABOLIC VARIOUS ANESTHETICS

Pathway

Dealkylation Dechlorination Enzyme induction

221

HYDROCARBONS

BREAKDOWN

OF

Metabolites identified” Trifluoroethanolamine, trifluoroacetaldehyde, trifluoroacetate, Cl, Br Chlorobromotrifluoroethane, chlorobromodifluoroethylene, Br, F Dichloroacetate, oxalate, Cl, F Methoxydifluoroacetate, oxalate, Cl, F Trifluoroethanol, trifluoroacetaldehyde, trifluoroacetate

Enflurane

Dealkylation Dehalogenation

Chlorofluoroacetate, oxalate, Cl, F Difluoromethoxy-ditluoroacetate, oxalate, Cl, F

Isoflurane

Dealkylation Dechlorination

Trifluoroacetate, Trichloroacetate,

Cl, F Cl, F

n Based on Figs. 4 to 9.

But now, the effects will be examined. In particular, the emphasis will be on cause/effect interrelations and the role of various factors that influence the metabolic impact. Two clinical anesthesia syndromes have received widespread attention during the past 15or-so years. These are termed “halothane hepatitis” and “methoxyflurane nephrotoxicity,” and have been discussed by the authors previously listed in Table 1. EFFECTS ON THE LIVER

Halothane hepatitis was the subject of a “National Halothane Study” in the United States (see Bunker, 1968), and has been called a “rare” disease. However, as shown in Table 7, this all depends on how one defines the word “rare.” Thus, while it is true that the overall rate (of occurrence) of Halothane hepatitis is l/30,000 or l/35,000 cases, this increases to about l/10,000 when halothane is used in a sequence with other anesthetics. In particular, note that the rate increases to 7/10,000 following multiple exposure to halothane. Note, also, that the incidence of postanesthesia jaundice during 1953-1956 (i.e., prior to halothane use) was 1l/10,000, but had increased to 41/10,000 during 1960- 1%3. It must also be pointed out that 18% of the patients exposed to halothane can develop hepatitis, and that the reported mortality rate among hepatic necrosis patients previously exposed to halothane was 46% (see Table 7). Table 8 presents the pattern of clinical symptomatology observed in halothaneassociated hepatitis. Note that this syndrome is seen primarily in women (especially obese ones) over 40 years of age. Postoperative fever is common, with jaundice and hepatitis usually appearing after 3 to 21 days postexposure. Also, as would be expected, multiple exposures to halothane increases the likelihood of adverse metabolic responses.

TABLE

7 HEPATOTOXICITY

l/30,000 (halothane vs total anesthesias) l/10,000 (halothane associated) 1.25/10,000 (halothane associated) 18% of 400 cases (1958- 1968) 7.1/10,000 (multiple exposure to halothane) 2.1/10,000 (exposed to other anesthetics) 7.1/10,000 3.0/10,000 2.4/10,000 0.7/10,000

7/10,000 (multiple exposure to halothane) 46% (139 of 300 cases during 1%3- 1976) ll/lO,OOO (during 1953- 1956) 42/10,000 (during 1960- 1963) 41/10,000 (halothane-associated,

Fatal hepatic necrosis and jaundice

Death from massive hepatic necrosis

Deaths from liver necrosis Hepatitis (following halothane use)

Massive hepatic necrosis

Massive hepatic necrosis

Hepatic necrosis Death among hepatic necrosis patients

Jaundice

1960- 1963)

(multiple halothane) (halothane and other anesthetics) (multiple nonhalothane anesthetics) (single anesthesia)

l/35,000 (halothane vs total anesthesias) l/10,000 (halothane and other anesthetics)

Incidence (and circumstances)

OF HALOTHANE-ASSOCIATED

Fatal massive hepatic necrosis

Type of toxic impact

INCIDENCE

Simpson et al., 1972

Sherlock, 1978

Dykes et al., 1972

Davis, 1972

Gottlieb and Trey, 1974

Rosenberg, 1972

Holaday and Fiserova-B.,

Simpson er al., 1972

Reference

1979

HALOGENATED

TABLE CLINICAL

SYNDROME

223

HYDROCARBONS 8

OF HALOTHANE-ASSOCIATED

HEPATITIS

Age

Any age, but predominantly

over 40 years.

Sex

Both sexes, females predominate.

Incidence

Not established. Presumed mortality 1:10,000 halothane anesthesias or 1: 1000 multiple exposures to halothane.

Clinical features

1. Multiple exposures, usually within 60 days. 2. Not dose related.” 3. Usually reported in patients without prior history of liver disease. 4. Course varies from anioteric hepatitis to massive hepatic necrosis. Can have cholestatic phase. 5. Unexplained postoperative fever is common. 6. Eosinophilia reported. 7. Jaundice and hepatitis-usually 3 to 21 days postexposure. 8. Cross-reactivity with methoxyflurane.

Pathology

Similar to viral or hepatotoxic hepatitis.

Mode of action

Halothane undergoes biotransformation. No animal model has reproduced complete syndrome. Hepatitis presumed by sensitization.

Source. Adapted from Gottlieb and Trey (1974). n See text.

Table 8 also mentions “cross-reactivity” of halothane with methoxyflurane. The methoxyflurane-induced hepatotoxicity is identical to that induced by halothane (Stein et al., 1972; Joshi and Conn, 1974). The entire hepatic syndrome appears indistinguishable from viral hepatitis, except that hepatitis antigen is not found in the serum (Dykes et al., 1972; Joshi and Conn, 1974). A few cases of fluroxene-associated hepatonecrosis have been reported, although only in patients who had received other medication known to induce liver microsomal enzymes (Fiserova-Bergerova, 1977). Anesthetic-associated hepatonecrosis causes increased levels of serum glutamic-pyruvic transaminase (SGPT) and/or serum glutamic-oxaloacetic transaminase (SGOT) in animals (Stein et al., 1972; Reynolds and Moslen, 1977; McLain et al., 1979; Jee et al., 1980) and also in humans (Wong et al., 1974; Trowel1 et al., 1975). This indicates hepatic dysfunction (Wong et al., 1974) with leakage from injured hepatic cells (Stein et al., 1972), and it has therefore been suggested that patients should be monitored for high serum levels of these transaminases (Trowel1 et al., 1975). In studies of halothane-associated hepatitis, several researchers have drawn attention to the usefulness of bromine analysis as an index of’halothane breakdown (Rehder et al., 1967; Stier, 1968; Atallah and Geddes, 1973; Cohen et al., 1975; Holaday, 1977). In this connection, Brown and Sipes (1977) cautioned that bromine release can have a soporific effect. As can be seen in Fig. 10, Mazze et aE.

224

J. R. MARIER

(1977) observed that serum inorganic bromide concentrations continued to increase during the 120-hr postanesthetic period (see also Malorino et al., 1980); furthermore, Mazze et al., (1977) warned that the accumulated concentration of about 3 meq/liter was close to the 6- to lo-meq range thought to be psychoactive. Similarly, Cohen and VanDyke (1977) discussed the fact that serum bromide levels can be as high as 2.5 meq after 9 days postanesthesia and can remain elevated for more that 22 days in some patients, i.e., “In a number of these individuals, bromide levels were in the sedative and possibly toxic ranges.” Considering the fact that the metabolic half-life of bromide is 12 days (Rehder et al., 1967; Mazze et al., 1977, Cohen and VanDyke, 1977), prolonged elevation of such metabolites in blood can only be attributed to ongoing release of halothane (or its derivatives) from storage sites in fat tissues. Obesity can be an important factor in the potentiation of adverse metabolic effects. Thus, obese persons retain more anesthetic (VanDyke, 1979), and prolonged storage in adipose tissues places obese persons at greater risk (Sherlock, 1978). In terms of specific anesthetics, it has been shown that “adipose” animals tend to have a fourfold higher-than-normal concentration of halothane in liver (Gostomzyk, 1972) and that obese people have the greatest fluroxene uptake (Gion et al., 1974) along with enhanced biotransformation of enflurane (Bentley et al., 1979) or methoxyflurane or halothane (Young et al., 1975). Another aspect of the obesity factor is that obese subjects tend to be hypoxia prone (Widger et al., 1976) and this stimulates fluoride release by means of the reductive pathway of halothane breakdown (Ross et al., 1979). In comparison with nonobese subjects, obese patients were found to have a fivefold greater level of serum inorganic fluoride following halothane anesthesia (Nawaf and Stoelting,

2.5-

,j 4,’ 0

4

htn-anesthess

62

6

l0

14

l6

26 HCWS

30

34

30

42

i ‘t;o

140

PosfaneslhesIa

FIG. 10. Mean inorganic bromide level in serum (solid line) and in urine (broken line) following halothane anesthesia. Reprinted, with permission, from Mazze et al. (1977).

225

HALOGENATEDHYDROCARBONS

1979; Young er al., 1975). In halothane-treated rats, the hypoxia factor can produce a lo- to 39-fold increase in serum inorganic fluoride (Widger ef al., 1976; Ross et al., 1979). Phenobarbital is known to be an activator of liver microsomal enzyme activity (cf. Cohen and VanDyke, 1977). However, in comparison with phenobarbital induction, the hypoxia factor was found to be the more potent stimulator of halothane hepatotoxicity (Ross et al., 1979; Jee et al., 1980). Recently, Ross et ai. (1979) commented that the National Halothane Study had overlooked hypoxia-prone patients, e.g., those with histories of sepsis or shock. To date, there is no simple explanation to account for anesthetic-associated hepatotoxicity. The general viewpoint is that none of the known metabolites (see Table 6) is responsible for the halothane syndrome. Thus, Cohen and VanDyke (1977) stated, . . the post-anesthetic period of slow release of the anesthetic from fat, back into the bloodstream, coincides with the time of highest proportionate amounts of anesthetic metabolism . . . (but) the precise mechanism, or mechanisms, accounting for this effect is not clear.

Similarly, Holaday and Fiserova-Bergerova (1979) commented that “mechanisms of toxicity are not fully understood.” Very recently, Cascorbi and Vento (1980) reported that a form of bromochlorotrifluoroethane (consult Fig. 5 and Table 6) is a “lethal compound,” whereas Loew and Goldblum (1980) proposed that reductive dechlorination-debromination of halothane leads to the formation of potentially toxic trifluoromethyl carbene. But whatever the specific mechanism [and as summarized by Cohen and VanDyke (1977)] the hepatotoxic effect of halogenated hydrocarbon anesthetics is the result of (i) accumulation of toxic metabolites; (ii) production of reactive intermediates (i.e., radicals); (iii) formation of haptens (see Fig. 4) leading to hypersensitivity responses.

or immune

The “hypersensitivity or immune response” aspect is a compelling one, especially in view of the enhanced incidence of hepatotoxicity following multiple exposures to halothane (see Table 7), along with the “cross-sensitization” with methoxyflurane mentioned in a preceding paragraph. As discussed by several reviewers (e.g., Cascorbiet al., 1971; Davis, 1972; Rehder and Sessler, 1974), it is likely that this syndrome is triggered particularly in “susceptible persons” who constitute a vulnerable subgroup among the total population. Such considerations have led Walton (1975) to suggest that persons with autoimmune disease are particularly at risk. Also, Sharpstone et al., (1971), Conn (1974), and Gottlieb and Trey (1974) have recommended that fluorinated anesthetics should be used with extreme caution (and perhaps contraindicated) in persons who have experienced prior adverse reactions to these anesthetics. So far, there has been no general agreement that the hepatotoxic effects of halothane obey a dose/response interrelation. In humans, one of the difficulties has undoubtedly been the factor of interindividual variability. One example of this is revealed in the work of Cascorbi et al. (1970) who showed that metabolic

226

J. R. MARIER

breakdown of halothane can vary from 2.4 to 17.3% in identical twins, and can differ from 2.9 to 70.0% in fraternal twins. Nevertheless, a dose/response mechanism has been reported for in vitro halothane inhibition of cell multiplication (Jackson, 1972); also, detrimental effects observed in several species of experimental animals have led to the conclusion that halothane “is a hepatotoxin in the classic sense” (Stevens et al., 1975); furthermore, in rat studies, correlation of halothane dosage with serum transaminase and hepatic cytochrome P-450 levels-along with resultant hepatotoxicity-led to the conclusion that Halothane is a “true hepatotoxin” (Jee et al., 1980). It is known that anesthetic-associated hepatotoxicity involves centrolobular necrosis (cf. Gottlieb and Trey, 1974), and that this can result in enlargement of the liver (Stier et al., 1972) with increased liver weight (Rietbrock and Richter, 1972). The primary effect is on the liver endoplasmic reticulum (Reynolds and Moslen, 1977) which undergoes proliferation (Gottlieb and Trey, 1974; Cohen and VanDyke, 1977), and this effect can be seen with as little as 1 hr of anesthetic exposure (Sindelar, 1976). EFFECTS

ON THE KIDNEY

In contrast with anesthetic-associated hepatotoxicity, a dose/response interrelation has been established for so-called “methoxyflurane nephrotoxicity” (Cascorbi, 1973; Gottlieb and Trey, 1974; Cohen and VanDyke, 1977; Holaday and Fiserova-Bergerova, 1979). Table 9 summarizes the symptomatological pattern encountered in this nephrotoxicity syndrome; and again, note the emphasis on obesity and other factors that potentiate the toxic manifestations. Anesthetic-associated nephrotoxicity is the result of enzymatically mediated defluorination, especially in anesthetics that have a F -c-c-oF group, such as is found in methoxyflurane and enflurane (as has been illustrated in Fig. 1). In humans, methoxyflurane defluorination is extremely rapid, i.e., beginning within 5 min after the onset of anesthetic administration (Weiss and decarlini, 1975); also, kidney damage can appear within a few days following methoxyflurane anesthesia (Cousins and Mazze, 1973). The mortality rate for methoxyflurane-associated nephrotoxicity was reported to be 50% (Hagood et al., 1973). It is relevant to mention that nephrotoxicity has been observed within 5 days following enflurane anesthesia in humans (Mazze et al., 1977). Figure 11 illustrates the comparative serum inorganic fluoride levels attained after anesthesia with four separate anesthetics. Note that the fluoride release is most extensive with methoxyflurane, followed by enflurane, then isoflurane; in comparison, little or no fluoride was released from halothane (Note: However, as previously discussed, hypoxic conditions increase the fluoride release from halothane by fivefold or more.) Figure 12 shows that phenobarbital-induced activation of microsomal enzymes increases the magnitude of fluoride release; this is

HALOGENATED

TABLE CLINICAL

SYNDROME

227

HYDROCARBONS 9 NEPHROPATHY

OF METHOXYFLURANE-ASSOCIATED

Age and Sex

Any.

Incidence

Mild syndromes and morbidity-common. Deaths reported. Incidence not known-may be rare. Associated hepatic necrosis in few patients.

Clinical features

1. Can occur with single or multiple exposure. 2. Probably dose related. 3. Nephrogenic diabetes insipidus. Low osmolality urine, polyuria, 24 liters/day, which does not respond to fluid restriction or antidiuretic hormone administration. 4. Dehydration and electrolyte loss in untreated patient. 5. Duration and severity-variable. Few days to years. Patients may need dialysis or renal transplant. Deaths reported. 6. May be associated with hepatic necrosis. 7. Aggravated by obesity, tetracycline, gentamicin, and prolonged administration of the anesthetic. 8. No demonstrable cross-reaction with halothane.

Pathology

Renal interstitial reaction; intratubular calcium oxalic” crystal deposition and fibrosis. Occasional glomerular and renal vascular lesions.

Mode of action

Methoxyflurane undergoes biotransformation. Metabolites, especially inorganic fluoride ion, affect renal tubules. Dose-related response. Tubular calcium oxalate crystal deposition is an aggravating cause.” Lesion reproduced in experimental animals.

Source. Adapted from Gottlieb and Trey (1974). ” See text.

0 COIlId

Halothane

lsofluranc

Enfluranc

Methon)

flurane

FIG. 11. Peak serum inorganic fluoride levels following anesthetic exposure to four fluorinated agents. Reprinted, with permission, from Cohen and VanDyke (1977).

228

J. R.

0

Control

m

Phenobarbital 1

0.0

MARIER

lsorlurane (n=4)

*SE

EnflU~Ile

(n=9)

Mcthoxyflurane

(n=9)

12. Effect of phenobarbital pretreatment on metabolic defluorination of isoflurane, enflurane, and methoxyflurane in Fisher-344 rats. Reprinted, with permission, from Greenstein et al. (1975). FIG.

especially noticeable with methoxyflurane, although the potentiation is also considerable with isoflurane. The effect of the obesity factor is illustrated in Fig. 13, where it can be seen that enflurane anesthesia in obese patients results in a serum inorganic fluoride level that is about twofold higher than in nonobese patients. Much the same pattern is shown for methoxyflurane in Fig. 14; in this illustration, the blood-borne fluoride was measured as “organic acid-labile fluoride” which serves as a reserve pool that eventually releases inorganic fluoride (Samuelson et al., 1976). Note that the serum level of labile organofluoride in obese patients can be as much as 55% higher and can remain elevated longer than in nonobese subjects; this reflects greater storage of methoxyflurane in fat, along with prolongation of its release in obese patients (Samuelson et al., 1976). Figure 15 summarizes the dose/response pattern for methoxyflurane-associated nephrotoxicity. It is important to note that this interrelation was based on peak serum inorganic fluoride levels, and-on this basis-indicated that the “threshold” for nephrotoxicity was associated with a peak serum F- level of 50 fl. However, reliance on “peak” serum F- levels can be misleading. For example, in rats treated with either methoxyflurane or inorganic fluoride, nephrotoxicity was associated with plasma F- levels of 20 PM (Roman et al., 1977). Also, in humans anesthetized with enflurane, the peak serum F- level was 33 PM; however, the

HALOGENATED Age MAC

HYDROCARBONS

(yrf

37.7 f 5.1 1.8 f 0.2

(hr) -*

Control

229

52.3 f 5.1 1.9 f 0.2

Serum Ionic

Fluoride

FIG. 13. Serum inorganic fluoride in obese and nonobese patients following enflurane anesthesia. Reprinted, with permission, from Bentley et al. (1979).

24-hr average of 15 pA4 was associated with a 25% reduction in “urine concentrating ability”; furthermore, a no-effect fluoride level was not achieved (Mazze et al., 1977). Therefore, nephrotoxicity is not only a function of peak serum F-, but rather, is a consequence of the overall duration of exposure; i.e., “the area under 1400-

5Cil.H OAlF

1300-

MOf-OwE

I'

,q, ',

) IZOOIIOO-

loo01st!!Y!!?A!F..-~

1000-

I' d I

p 4 '!&"

: : : ?

!

FIG. 14. Serum “organic acid-labile” fluoride in nonobese and obese patients following methoxyflurane anesthesia. Reprinted, with permission, from Samuelson ef al. (1976).

230

J. R.

MARIER

2Sc IT .

PCtVURlC RENAL FAILURE. ONE PATIENT MD (TAVES et .I *’ )

240 ,= z

200

I

P 3 IA. 3 e m f

CLlNlCAL

IO

I

CLINICAL

120

L z Y

LASORATORV so

fTHRE$HOLD

40

I

NEPHROTOXlCllY

EVIDENCE

OF NEPHROTOXlClTV

NO NEPliPROlOXlClTV NO NEPHROTOXICITV

NEPHROTOXlClTV

(MAZZE et al 16 )

(CCUSINS

& MAi’LE

“)

ONLV (MAZZE et al ‘)

(COUSINS

6 MAZZE

4”)

- SURGERY WllH CPS (COUSINS ., 41 3’) - GEM. SURG. PATIENTS KiOlJSINS L MAUE “)

0’ DEGREE OF NEPHROTOXlClTV

moJ

+ =OS

MAC -1.0 MAC * =I.5 MAC

:‘: =Subclinical Toxicity =Mild Clinical Toxicity q Clinical Toxicity 8

l

160-

@

0 ‘0

0 0

I

, 2

I

I 4

MAC Hours,

I

0

I

1 6

’

I 10

Methoxyflurane

FIG. 15. Dose/response interrelations for methoxyflurane in humans. Reprinted, with permission, from (top) Mazze and Cousins (1973) and (bottom) Cousins and Mazze (1973).

the curve” (Mazze et al., 1977), “the area under the peak trend” (Mazze et al., 1979). Confirmation of the dose/response interaction is shown in Fig. 16, where it can be seen that diuresis was enhanced by methoxyflurane or by sodium fluoride; in contrast, the injection of oxalic acid (at a dosage similar to that resulting from methoxyflurane metabolism) produced no abnormality. There is also evidence showing that abnormal diuresis is a direct function of the duration of methoxyflurane anesthesia (Fig. 17) and, also, of plasma inorganic fluoride level (Fig. 18); and again, there is no indication of any obvious “no-effect” threshold.

HALOGENATED

8.0

m

Urine

0

u+v l

p-CO.05

volume

(pre- versus

231

HYDROCARBONS .

posttreatment)

:

2.C

C FIG. 16. Diuretic effect of sodium fluoride (NaF) or methoxyflurane (MF), and lack of effect of oxalate (OA), in comparison with controls(C). Reprinted, with permission, from Cousins et al. (1974).

Figure 19 shows that patients with clinically evident renal dysfunction have higher serum F- levels than those seen in nonclinical cases, thereby indicating an impaired renal excretion of fluoride, along with concomitant bioaccumulation. It has been stated that enflurane should be avoided in patients who have renal impairment (Cousins, 1980), and the same restriction no doubt applies to the use of methoxyflurane. The anesthetic-associated nephrotoxicity syndrome resembles “nephrogenic occurring simultaneously diabetes insipidus,” i.e., with serum hyfierosmolality with polyuric hypoosmolality, along with the excessive thirst of polydipsia. How-

FIG. 17. Enhanced diuresis as a direct function of duration of methoxyflurane anesthesia in humans. Plotted from the data of Urgena and Gergis (1973).

J. R. MARIER

232

I’ 100

200

PLASMA

300

F, ,&l/L

FIG. 18. Enhanced diuresis as a direct function of plasma inorganic fluoride level in rats. Plotted from the data of Whitford and Taves (1971).

ever, unlike diabetes insipidus, anesthetic-associated nephrotoxicity does not involve a deficiency of vasopressin antidiuretic hormone-and indeed-is vasopressin resistant, thereby indicating a renal lesion of the distal nephron induced by fluoride (Cousins and Mazze, 1973; Gottlieb and Trey, 1974). This process, once begun, is autocatalytic because the afflicted persons tend to retain a higherthan-normal proportion of the fluoride body burden. CHRONIC EXPOSURES

Aside from outright anesthesia, it is relevant to point out that enflurane (Wickstrom et al., 1977a, 1977b) and methoxyflurane (Wilson et al., 1972; Creas-------

MFMF-

clinical nephrotoxicity Lab evidence only

1 +_ S.E. of mean

prew MF

I DOYS

CllnlCQl P
MF

<0.05

CO.01

Postoperative
co.01

co.1

co.05

L%

FIG. 19. Mean daily serum inorganic fluoride concentrations in patients with clinical nephrotoxicity patients (bottom line), following methoxyflurane anesthesia. Reprinted, with permission, from Mazze ef al. (1971).

(top line) and in “control”

HALOGENATED

233

HYDROCARBONS

ser et al., 1974; Clark et al., 1976; Fiserova-Bergerova, 1976; Young et al., 1976; Palahniuk et al., 1977) have been used as analgesics in obstetrics. There have also been reported instances of addictive sniffing of halothane (Guynn and Faillace, 1978) and methoxyflurane (Klemmer and Hadler, 1978) associated with rather dire consequences. Epidemiological studies have indicated that low-dose long-term occupational exposures to anesthetic environments (see Table 10) may lead to serious metabolic effects. In Table 11, note that the metabolic aberrations are a direct function of the intensity of exposure; also note that there is a “carrier” effect; i.e., wives of exposed dentists have a 78% higher-than-normal rate of spontaneous abortion, whereas unexposed wives of male anesthetists experience a 25% higher-thannormal rate of fetal congenital malformations. As for the nature of the occupational effects, hepatotoxicity has already been discussed in preceding segments of this presentation, i.e., particularly in connection with halothane and its cross-reactivity with methoxyflurane, and also in connection with fluroxene. The topic of congenital fetal abnormalities is more elusive, although Garro and Phillips (1977, 1978) have reported the in vitro mutagenicity of bromochlorodifluoroethylene, i.e., a breakdown product of reductive halothane metabolism (consult Fig. 5 and Table 6). Furthermore, in a study with rats, Popova et al. (1979) reported that a subanesthetic concentration of halothane induced embryonic deaths associated with early interruption of pregnancy and

ANESTHETIC

Anesthetic Halothane”

Methoxyflurane*

CONCENTRATIONS

TABLE

10

REPORTED

IN

THE AIR OF OPERATING ROOMS

Concentration (wm) 0.03-0.45 o-49 Trace-290 9 86 120-14,200 1000 l-10 10-30 27 (peak) 85 (average) >73 (hospital dental clinic) 0.01.5-0.095 1.3-9.8 l-2 (near surgeon) 2-10 (near anesthetist)

Reference Spierdijk, 1972

Stevens et al., 1975 Uehleke et al., 1977 Vaughan et al., 1978

Spierdijk, 1972 Vaughan et al., 1978

n In 35-day studies with experimental animals, Stevens et a/. (1975) observed liver injury at halothane airborne concentrations of 15 and SO ppm. Also, Halsey (1978) has recommended that the long-term airborne concentration of halothane should not exceed an average of 5 ppm. * Halsey (1978) has recommended that the long-term airborne concentration of methoxyflurane should not exceed an average of 5 ppm.

234

J. R. MARIER

METABOLIC

EFFECTS

TABLE 11 OF LOW-DOSE LONG-TERM OCCUPATIONAL ANESTHETIC ENVIRONMENTS

Types of subjects compared Exposed

dentists vs controls

Metabolic

EXPOSURES

aberration

Liver disease

TO

Increased incidence (n-fold) 2.56

Exposed females vs nonexposed females Male anesthetists vs male pediatricians

Hepatic disease (excluding serum hepatitis)

Female physician anesthetists vs controls Operating-room nurses vs controls

Spontaneous

abortion

3.8 3.0

Active female anesthetists Active female anesthetists

vs same group, preemployment vs retired female anesthetists

Spontaneous

abortion

2.0 1.33

Wives of exposed dentists

vs controls

Spontaneous

abortion

1.I8

Female physician Exposed Unexposed

anesthetists

nurse anesthetists

vs unexposed vs unexposed

wives of male anesthetists

Nurse anesthetists Female physician

female physicians nurses

vs controls

vs controls anesthetists

vs unexposed

female pediatricians

Source. Tabulated from Vaughn et al. (1978); also Cohen and VanDyke 0 Does not apply to exposed males.

Fetal congenital abnormalities Fetal abnormalities

1.3 to 2.2

2.0 1.6

Fetal congenital malformations

1.25

Malignancy” (reticuloendothelial and lymphoid)

3.0

Malignancy* (reticuloendothelial and lymphoid)

2.0

(1977).

decreased fertility. And, regarding the malignancy topic, Waskell(1978) has illustrated the structural similarities between halogenated hydrocarbon anesthetics and known carcinogenic compounds (see Fig. 20). In the latter connection, Vaughan et al. (1978) have made a pertinent comment: It is both interesting and disconcerting to know that vinyl chloride . . was once considered for use as an anesthetic. It was discarded because of its myocardial irritant properties. Perhaps even more disquieting is the structural similarity between the anesthetic trichloroethylene and vinyl chloride.

(Note: Again, consult Fig. 20.) Of particular relevance to this report is the question of how the preceding pattern(s) might relate to the topic of chlorinated hydrocarbons, especially with regard to the role of liver microsomal enzymes. Cohen and VanDyke (1977) and Poppers (1980) have discussed microsomal enzymes in relation to various chemicals, including halogenated anesthetics. But, in the present context, perhaps it is most pertinent to mention some aspects of possible “cross-sensitization” involving chlorinated hydrocarbons and fluorinated anesthetics. Conney and Burns (1972) discussed chlorinated hydrocarbon compounds in terms of their role as microsomal enzyme inducers, as well as their potential carcinogenicity, their possible role in impaired reproduction, and their capacity to induce jaundice. They also commented: “Examples of insecticides that stimulate

HALOGENATED

235

HYDROCARBONS INHALATION ANESTHETICS

CARCINOGENS F I F-C-C-Cl

Br I

! ? Holothane Cl I H-C-O-C-H

Cl I

I H ? Bis(chloromethyl)Ether Cl i

? Chloromethyl

? Methyl Ether Cl

H

B

I Ether

11

H-C-C-O-C-C-H b 6 Bir (a-chloroethyl)

(Fluothone) i

!A ! Isoflurone(Forone) Cl

I H-C-O-C-H

ii’

F Cl I I F-C-C-O-C-H

F

I I H-C-C-O-C-H

I I

Cl F Yethoxytlurone

i

? (Penthrone)

+~-~-,d-~-H Jl! Entlurane

1 (Ethrane)

“\-c/c’

cic~c/c’

H’

H/ ‘Cl Trichloroet hylene

‘H Vinyl Chloride

FIG. 20. Structure of commonly used contemporary anesthetics, compared with chemically similar carcinogens. Reprinted, with permission, from Waskell (1978).

drug metabolism (in rats) include Chlordane, DDT, Methoxychlor, Aldrin, Endrin, Dieldrin, Heptachlor. . . .” It is known that halothane hepatotoxicity is potentiated by prior exposure to arochlor PCB (Reynolds and Maslen, 1977; Cohen and VanDyke, 1977). And similarly, fluroxene hepatotoxicity is potentiated by PCB (Murphy et al., 1979) as well as by mirex (Murphy et al., 1980). There is also this comment by Cohen and VanDyke (1977) on the PCB topic: “Because of the wide distribution of this pollutant in our environment, it would seem likely to exert an inductive effect in man.” As regards methoxyflurane-associated nephrotoxicity, Stoelting and Peterson (1975) wondered if “enzyme induction from dietary or inhaled pollutants” might be a contributing factor (see also Jaramillo and Cummings, 1979). Moreover, Mazze and Cousins (1973) asked: “Will enzyme induction in man, due to exposure to various chemical substances such as barbiturates, tranquilizers, insecticides, aerosol sprays . . . exacerbate renal toxicity. . . ?” This question-along with other questions posed in this report-might best be answered by a partial quote taken from the Cohen and VanDyke statement in the preceding paragraph: “. . . it would seem likely. . . .” ACKNOWLEDGMENTS Sincere thanks are expressed to Lynda Boucher, Roger Levesque, and Harry Turner for their assistance in the preparation of this report.

236

J. R. MARIER

REFERENCES Atallah, M. M., and Geddes, I. C. (1973). Metabolism of halothane during and after anesthesia in man. Brit.

J. Anaesrh.

45, 464-470.

Bentley, J. B., Vaughan, R. W., Miller, M. S., Calkins, J. M., and Gandolfi, A. J. (1979). Serum inorganic fluoride levels in obese patients during and after enflurane anesthesia. Anesth. Analg. 58, 409-412. Brown, B. R., and Sipes, I. G. (1977). Biotransformation and hepatotoxicity of halothane. B&hem. Pharmacol. 26, 2091-2094. Bunker, J. P. (1968). Final report of the National Halothane Study. J. Anesrhesiol. 29, 231-232. Cascorbi, H. F., Vesell, E. S., Blake, D. A., and Helrich, M. (1970). Genetic and environmental influence on Halothane metabolism in twins. C/in. Pharmacol. Ther. 12, 50-S. Cascorbi, H. F., Vesell, E. S., Blake, D. A., and Helrich, M. (1971). Halothane biotransformation in man. Ann. N.Y. Acad. Sci. 179, 244-248. Cascorbi, H. F. (1973). Biotransformation of drugs used in anesthesia. Anesthesiology 39, 115- 125. Cascorbi, H. F., and Vento, J. M. (1980). Toxic properties of an isomer of halothane. Anaesthesisr 29, 169- 171. Clark, R. B., Beard, A. G., Thompson, D. S., and Barclay, D. L. (1976). Maternal and neonatal plasma inorganic fluoride levels after methoxyflurane analgesia for labor and delivery. Anesthesiology 45, 88-91. Cohen, E. N., Trudell, J. R., Edmunds, H. N., and Watson, E. (1975). Urinary metabolites of halothane in man. Anesthesiology 43, 392-401. Cohen, E. N., and VanDyke, R. A. (1977). “Metabolism of Volatile Anesthetics.” Addison-Wesley, Reading, Mass. Conn, H. 0. (1974). Halothane-associated hepatitis. Isr. J. Med. Sci. 10, 404415. Conney, A. H., and Bums, J. J. (1972). Metabolic interactions among environmental chemicals and drugs. Science 178, 576-586. Cousins, M. J., and Mazze, R. I. (1973). Methoxyflurane nephrotoxicity. J. Amer. Med. Assoc. 225, 1611-1616. Cousins, M. J., Mazze, R. I., Kosek, J. C., Hitt, B. A., and Love, F. V. (1974). The etiology of methoxyflurane nephrotoxicity. J. Pharmacol. Exp. Ther. 190, 530-541. Cousins, M. J. (1980). Halothane hepatitis: What’s new? Drugs 19, l-6. Creasser, C. W., Stoelting, R. K., Krishna, G., and Peterson, C. (1974). Methoxyflurane metabolism and renal function after methoxyflurane analgesia during labor and delivery. Anesthesiok~gy 41,62-66. Dahlgren, B. E. (1979). Fluoride concentrations in urine of delivery-ward personnel following exposure to low concentrations of methoxyflurane. J. Occap. Med. 21, 624-626. Davis, J. E. (1972). Fatal hepatic necrosis associated with halothane anesthesia. Amer. J. Obstet. Gynecol. 112, 967-971. Duncan, W. A. M.. and Raventos, J. (1959). The pharmacokinetics of halothane anesthesia. Brif. J. Anaesfh. 31, 302-315. Dykes, M. H. M., Gilbert, J. P., Schur, P. H., and Cohen, E. N. (1972). Halothane and the liver-A review of the epidemiologic, immunologic, and metabolic aspects of the relationship. Canad. J. Surg. 15, 217-238. Feingold, A., and Holaday, D. A. (1977). The pharmacokinetics of metabolism of inhalation anesthetics. Brit. J. Anaesth. 49, 155- 162. Fiserova-Bergerova, V. (1976). Fluoride in bone of rats anesthetized during gestation with enflurane or methoxyflurane. Anesthesiology 45, 483-486. Fiserova-Bergerova, V. (1977). Species differences in metabolism and toxicity of fluroxene. Xenobiotica 7, 113- 114. Garro, A. J., and Phillips, R. A. (1977/1978). Mutagenicity of the halogenated oletin 2-bromo-2chloro-1, I-difluoroethylene, a presumed metabolite of the inhalation anesthetic halothane. (Part 1, 1977) Environ. Health Perspect. 21, 65-69. (Part 2, 1978) Mutat. Res. 54, 17-22. Gion, H., Yoshimura, N., Holaday, D. A., Fiserova-Bergerova, V., and Chase, R. E. (1974). Biotransformation of fluroxene in man. Anesthesiology 40, 553-562. Gostomzyk, J. G. (1972). Uber die Aufnahme lipoidloslicher Kohlenwasserstoffe als indikator fur die

HALOGENATED

HYDROCARBONS

237

Durchblutung

von Fettgewebe und uber die Steigerumg ihrer Toxizitat bei Leberverfettung. Z. Biochem. 10, 521-527. Gottlieb, L. S., and Trey, C. (1974). The effects of fluorinated anesthetics on the liver and kidneys. Annu. Rev. Med. 25, 411-429. Greenstein, L. R., Hitt, B. A., and Mazze, R. I. (1975). Metabolism in vitro of enflurane, isoflurane. and methoxyflurane. Anesthesiology 42, 420-424. Guynn, R. W., and Faillace, L. A. (1978). Organic fluorides-Implications for psychiatry. J. C’Iin. Psychiat. 39, 523-531. associated with Hagood, C. O., Klemmerer, W. T., and Jackson, B. (1973). Nephrotoxicity methoxyflurane anesthesia. Amer. J. Surg. 125, 786-788. Halsey, M. J. (1978). Maximum safe levels of anesthetic contamination in operating-rooms. Proc. Anaesth. Res. Sot. 50, 633-P. Holaday, D. A. (1977). Absorption, biotransformation, and storage of halothane. Environ. Health Klin.

Chem.

Perspect.

Klin.

21, 165-

169.

Holaday, D. A., and Fiserova-Bergerova, V. (1979). Fate of fluorinated anesthetics in man. Drug Metabol. Rev. 9, 61-78. Jackson, S. H. (1972). The metabolic effects of halothane on mammalian hepatoma cells in vitro. Anesthesiology

37, 489-492.

Jaramillo, J., and Cummings, J. R. (1979). Assessment of the anesthetic and metabolic activities of dioxychlorane, a new halogenated volatile anesthetic agent. Brit. J. Anaesth. 51, 1041- 1049. Jee, R. C., Sipes, G., Gandolfi, A. J., and Brown, B. R. (1980). Factors influencing halothane hepatotoxicity in the rat hypoxic model. Toxicol. Appl. Pharmacol. 52, 267-277. Joshi, P. H., and Conn, H. 0. (1974). The syndrome of methoxyflurane-associated hepatitis. Ann. Intern.

Med.

80, 395-401.

Klemmer, P. J., and Hadler, N. M. (1978). A consequence of abuse of an organofluoride anesthetic. Ann. Intern. Med. 80, 395-401. Loew, G., Motulsky, H., Trudell, J., Cohen, E., and Hjelmeland, L. (1974). Quantum chemical studies of the metabolism of the inhalation anesthetics methoxyflurane, enflurane, and isoflurane. Mol. Pharmacol.

10,406-418.

Loew, G., and Goldblum, A. (1980). Electronic spectrum of model cytochrome P-450 complex, with postulated carbene metabolite of halothane. J. Amer. Chem. Sot. 102, 3657-3659. Malorino, R. M., Gandolfi, A. J., and Sipes, I. G. (1980). Gas-chromatographic method for the halothane metabolites, trifluoroacetic acid, and bromide, in biological fluids. J. Anal. Toxicol. 4, 250-254. Mathieu, A., DiPadua, D., Kahan, B. D., and Mills, J. (1975). Humoral immunity to a metabolite of halothane, fluroxene, and enflurane. Anesthesiology 42, 612-616. Mazze, R. I., Trudell, J. R., and Cousins, M. J. (1971). Methoxyflurane metabolism and renal dysfunction. Anesthesiology 35, 247-252. Mazze, R. I., and Cousins, M. J. (1973). Renal toxicity of anesthetics, with specific reference to the nephrotoxicity of methoxyflurane. Canad. Anaesth. Sot. J. 20, 64-80. Mazze, R. I. (1976). Methoxyflurane nephropathy. Environ. Health Perspect. 15, Ill119. Mazze, R. I., Calverley, R. K., and Smith, N. T. (1977). Inorganic fluoride nephrotoxicity. Anesthesiology

46, 265-271.

Mazze, R. I., Beppu, W. J., and Hitt, B. A. (1979). Metabolism of synthane-Comparison within vivo and in vitro defluorination of other halogenated hydrocarbon anaesthetics. Brit. J. Anaesth. 51, 839-844. McLain, G. E., Sipes, I. G., and Brown, B. R. (1979). An animal model of halothane hepatotoxicity. Anesthesiology 51, 321-326. Murphy, M. J., Piper, L. J., Fasco, M. J., Cashin, M. J., McMartin, D. N., and Kaminsky, L. S. (1979). Potentiation of fluroxene toxicity with polychlorinated biphenyls. Toxicol. Appl. Pharmacol.

48, 87-97.

Murphy, M. J., Piper, L. J., McMartin, D. N., and Kaminsky, L. S. (1980). The role of cytochrome P-450 inducing agents in potentiating the toxicity of fluroxene. Toxicol. Appl. Pharmacol. 52, 69-81.

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