Arvind K. Chaturvedi

Civil Aerospace Medical Institute

Federal Aviation Administration

Oklahoma City, OK 73125

April 2009

Final Report

Aerospace Toxicology:

An Overview

DOT/FAA/AM-09/8

Office of Aerospace Medicine

Washington, DC 20591

OK-09-0434-JAH

Federal Aviation

Administration
NOTICE

This document is disseminated under the sponsorship 

of the U.S. Department of Transportation in the interest 

of information exchange. The United States Government 

assumes no liability for the contents thereof.

___________

This publication and all Office of Aerospace Medicine 

technical reports are available in full-text from the Civil 

Aerospace Medical Institute’s publications Web site: 

www.faa.gov/library/reports/medical/oamtechreports


Technical Report Documentation Page 

1. Report No. 2. Government Accession No. 3. Recipient's Catalog No. 

DOT/FAA/AM-09/8 

4. Title and Subtitle 5. Report Date 

Aerospace Toxicology: An Overview April 2009 

6. Performing Organization Code 

 

7. Author(s) 8. Performing Organization Report No. 

Chaturvedi AK 

9. Performing Organization Name and Address 10. Work Unit No. (TRAIS) 

FAA Civil Aerospace Medical Institute 

P.O. Box 25082 11. Contract or Grant No. 

Oklahoma City, OK 73125 

12. Sponsoring Agency name and Address 13. Type of Report and Period Covered 

Office of Aerospace Medicine 

Federal Aviation Administration 

800 Independence Ave., S.W. 

Washington, DC 20591 14. Sponsoring Agency Code 

15. Supplemental Notes 

This work was accomplished under the approved task AM-B-09-TOX-202. 

16. Abstract 

The field of aerospace toxicology is composed of aerospace and toxicology. The term aerospace—that is, the 

environment extending above and beyond the surface of the Earth—is also used to represent the combined 

fields of aeronautics and astronautics. Aviation is another term frequently and interchangeably used with 

aerospace and aeronautics and is explained as the science and art of operating powered aircraft. Toxicology is 

the basic science of poisons. It deals with the adverse effects of substances on living organisms. Any substance 

could be poisonous, depending upon its exposure amount and frequency. 

Although toxicology borrows knowledge from the fields of biology, chemistry, immunology, pathology, 

physiology, and public health, the most closely related field to toxicology is pharmacology. Economic 

toxicology, environmental toxicology, and forensic toxicology are 3 main branches of toxicology. Toxicology is 

a multidisciplinary field. Aerospace toxicology could be considered closely related to aerospace medicine. 

In this overview, a literature search for the period of 1960–2007 was performed, covering aerospace toxicologyrelated subject matter. The article is divided into the sections of introduction, agricultural aviation (aerial 

application), aviation combustion toxicology, postmortem aviation forensic toxicology, cabin air 

contamination, and references. Further readings are also suggested. It is anticipated that this overview article 

would be a reference source for the topics related to aerospace toxicology. 

 

17. Key Words 18. Distribution Statement 

 

 

Aerospace Toxicology, Aerial Application, Combustion

Toxicology, Aviation Forensic Toxicology, Cabin Air 

Quality, Pilot Fatalities, Aviation Accident Investigation

Document is available to the public through the 

Defense Technical Information Center, Ft. Belvoir, 

VA 22060; and the National Technical Information 

Service, Springfield, VA 22161 

19. Security Classif. (of this report) 20. Security Classif. (of this page) 21. No. of Pages 22. Price 

Unclassified Unclassified 48 

Form DOT F 1700.7 (8-72) Reproduction of completed page authorized 

iii

ACKNOWLEDGMENTS

The author is grateful to Kristi J. Craft for assisting in the compilation of references and for providing 

critical remarks and suggestions in the organizational and grammatical structures of the manuscript.

SYMBOLS, ABBREVIATIONS, AND ACRONYMS 

λ ------------------------ (lambda) wavelength 

2,4-D ------------------ dichlorophenoxyacetic acid 

5-HIAA --------------- 5-hydroxyindole-3-acetic acid 

5-HTOL --------------- 5-hydroxytryptophol 

AAFS ----------------- American Academy of Forensic Sciences 

AsMA ----------------- Aerospace Medical Association 

C ----------------------- concentration 

CAA ------------------- Civil Aviation Authority 

CAEE -------------------- average effective exposure concentration 

CAMI ----------------- Civil Aerospace Medical Institute 

CBI -------------------- 1-cyano-2-benzoisoindole (1-cyano[f]benzoisoindole) 

CFR ------------------- Code of Federal Regulations 

CN ̄ ------------------- cyanide ion 

CO --------------------- carbon monoxide 

CO2 -------------------- carbon dioxide 

cyano-MetHb --------- cyanomethemoglobin 

DDT ------------------- dichlorodiphenyltrichloroethane 

EUROCAE------------ European Organisation for Civil Aviation Equipment 

FAA ------------------- Federal Aviation Administration 

FED ------------------- Fractional Effective Dose 

FTC -------------------- Fractional Toxic Concentration 

GAO ------------------- General Accounting Office 

HbA1c ------------------ hemoglobin A1c

HCN ------------------- hydrogen cyanide 

HEPA: ---------------- high efficiency particulate air 

HHb ------------------- deoxyhemoglobin 

K ----------------------- constant 

MetHb ----------------- methemoglobin 

NTSB ----------------- National Transportation Safety Board 

OxyHb ---------------- oxyhemoglobin 

PCR ------------------- polymerase chain reaction 

ppm -------------------- parts per million 

SOFT ------------------ Society of Forensic Toxicologists, Inc. 

SSRIs ------------------ selective serotonin reuptake inhibitors 

sulph-MetHb --------- sulphmethemoglobin 

t ------------------------ gas exposure time 

TCPs ------------------ tricresyl phosphates 

td ----------------------- time-to-death 

tHb --------------------- total hemoglobin 

THC ------------------- Δ9

- tetrahydrocannabinol 

ti ------------------------ time-to-incapacitation 

TMPP ----------------- trimethyl propane phosphate 

TSB -------------------- Transportation Safety Board of Canada 

vii

Contents

1 INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2 AGRICULTURAL AVIATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2.1 Generality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2.2 Pesticidal Toxicology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2.3 Multi-Agricultural Chemicals and Organic Solvents/Surfactants . . . . . . . . . . . . . . . . . . . . . . . . 2

2.4 Application Safety. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2.5 Exposure Monitoring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

3 AVIATION COMBUSTION TOXICOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

3.1 Combustion, Fire, and Smoke. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

3.2 Smoke Gases and Toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

3.3 Aircraft Material Testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

3.4 Gases and Their Interactive Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

 3.4.1 Gas Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

 3.4.2 Fractional Effective Dose (FED). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

 3.4.3 Carboxyhemoglobin (COHb) and Blood Cyanide Ion (CN ̄) . . . . . . . . . . . . . . . . . . . . 10

 3.4.4 COHb and Blood CN ̄ Interactive Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

 3.4.5 COHb and Blood CN ̄ in Fire-Involved Aircraft Accident Fatalities. . . . . . . . . . . . . . . . 15

 3.4.6 Analytical Results Interpretation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

 3.4.6.1 Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

 3.4.6.2 COHb Concentrations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

 3.4.6.3 CN ̄ Concentrations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

 3.4.6.4 MetHb, Cyano-MetHb, and Sulfmethemoglobin (Sulf-MetHb). . . . . . . . . . . . . 16

4 POSTMORTEM AVIATION FORENSIC TOXICOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

4.1 Introductory Comments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

4.2 Analytical Components. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

4.3 COHb and Blood CN ̄ Concentrations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

4.4 Ethanol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

4.5 Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

 4.5.1 Commonly Used and Abused Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

 4.5.2 SSRIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

 4.5.3 First-Generation H1 Antihistaminics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

 4.5.4 Other Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

 4.5.4.1 Selegiline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

 4.5.4.2 Sildenafil. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

 4.5.4.3 Vardenafil. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

 4.5.4.4 Butalbital. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

4.6 Elevated Glucose and HbA1c. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

5 CABIN AIR CONTAMINATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

5.1 Introductory Aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

5.2 Aircraft Cabin Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

5.3 Space Vehicle Cabin Air. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

5.4 Aircraft Engine Oils, Hydraulic Fluids, and Lubricants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

6 REFERENCES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Aerospace Toxicology: An Overview

All substances are poisons; there is none which is not a poison. 

The right dose differentiates a poison from a remedy.

—Paracelsus

1 INTRODUCTION

Aerospace toxicology is composed of 2 words, aerospace 

and toxicology. The former could be denoted as “the total 

environment extending above and beyond the surface of 

the planet Earth” (28). Aerospace is also used to represent 

the combined fields of aeronautics and astronautics. The 

field of aeronautics is the art and science of flight through 

the atmosphere (28), whereas astronautics is a relatively 

new field related to the art and science of space flight (26). 

Aviation is another term frequently and interchangeably 

used with aerospace and aeronautics and is explained as 

the science and art of operating powered aircraft (269). 

Toxicology is the basic science of poisons. It deals with 

the adverse effects of substances on living organisms. 

Any substance could be poisonous, depending upon its 

exposure amount and frequency (106, 125, 182).

Toxicology borrows knowledge from the fields of 

biology, chemistry, immunology, pathology, physiology, and public health. The most closely related field 

to toxicology is pharmacology (182). The toxicology 

field can easily be branched into economic toxicology, 

environmental toxicology, and forensic toxicology. In 

view of the multidisciplinary nature of toxicology, one 

can deduce that aerospace toxicology is closely related to 

aerospace medicine, which is a specialty field of general 

medicine (27) and is concerned with the health and medical problems of man in aviation and space flights (199). 

Alternatively, aviation medicine could be considered as 

the branch of preventive medicine that deals with the 

special problems of flying, both within and outside the 

atmosphere (46). 

In this overview, a literature search for the period of 

1960–2007 was performed covering aerospace toxicologyrelated subject matter. In addition to the introduction, 

the article is divided into headings of agricultural aviation (aerial application), aviation combustion toxicology, 

postmortem aviation forensic toxicology, and cabin air 

contamination. At the end of the references section, further 

readings are also suggested. This article is anticipated to 

be an informative resource for subject matter associated 

with aerospace toxicology.

2 AGRICULTURAL AVIATION 

2.1 Generality

Use of aerial application is increasing throughout 

the world to increase food production. The application 

process involves spraying of pesticides, herbicides, growth 

modifiers, fertilizers, and other agricultural chemicals on 

crops. Many of these chemicals are poisonous to human 

beings, causing serious signs/symptoms and possibly 

death (210). Incidents and accidents involving aerial 

applications and handling of commercial agricultural 

chemical preparations (formulations) do occur. Some 

examples are: (i) an experienced aerial applicator pilot, 

who accidentally spilled parathion on his clothes while 

pouring the concentrate from a 55-gallon drum 4 d earlier 

and who afterwards became irritable and introverted, 

was not feeling well and had a headache on the day he 

crashed his plane; (ii) a pilot, who was exposed to drift-

ing parathion and required atropine therapy, flew into 

a tree during pull-up; (iii) an aircraft connector became 

loose after take-off and sprayed a mixture containing 

parathion in the pilot’s face, saturating his body with the 

spray, causing him to lose control of the plane, which 

crashed; and (iv) a pilot was splashed with a defoliant 

during a flight, which caused a crash, almost resulting in 

the pilot’s death (191). Such accidental exposures and the 

development of aerial dust allergies in pilots were topics 

of a group discussion on protecting agriculture pilots 

(191). In general, these agricultural chemicals are toxic 

(89, 109), and if occupational safety and precautionary 

measures are not properly taken, exposures of applicator 

personnel and agricultural aircraft accident investigators to 

such chemicals could lead to acute or chronic poisonings. 

Poisonings of agricultural pilots may, thus, contribute to 

aviation accidents, as well. These poisonings could be the 

result of exposures to a single chemical or to multiple 

chemicals (or chemical mixtures).

2.2 Pesticidal Toxicology

Toxicological aspects of organophosphorus and 

organochlorine insecticides have been elaborated in 

the literature (89, 168). Although not used anymore, 

dichlorodiphenyltrichloroethane (DDT) is the most 
studied organochlorine insecticide and has also served 

as a prototype for the toxicological properties of other 

organochlorine insecticides (89, 168). Organophosphorus and organochlorine chemicals adversely affect 

the functions of the central nervous system. Behavioral 

difficulties have been implicated in aerial applicators following exposures to pesticides (100, 101, 171, 257, 299). 

Signs/symptoms of anxiety, uneasiness, depression with 

weeping, dizziness, emotional liability, frequent and severe 

disagreement with family and coworkers, and being unable 

to perform familiar tasks were reported during medical 

evaluations of 2 agricultural pilots actively engaged in the 

aerial application of organophosphorus/organochlorine 

insecticides, methyl parathion, DDT, toxaphene, endrin, 

and dieldrin (100, 101). Toxicological evaluation of postmortem samples from pilots killed while engaged in aerial 

application revealed that blood cholinesterase levels in 

44 of 104 pilots (165) and 77 of 130 pilots (166) were 

below the normal range, suggesting a problem of acute 

and/or chronic toxicity from organophosphorus pesticides 

applied by agricultural aircraft. Reduced plasma cholinesterase levels were found in 2 agriculture pilots involved 

in non-fatal aviation accidents (98, 99). Accidents and 

poisonings in aerial applications have been documented 

(97-99). Aerial application-related precautions, signs and 

symptoms of pesticide poisonings, and their treatments 

are summarized for protecting the agricultural pilots (97, 

191). These findings suggested that better educational 

efforts could reduce the accidents in this sector of the 

agricultural activity. 

For an aerial spraying program to manage insect epidemics in large tracts of forest, extensive studies have been 

conducted of the toxicology of insecticides (fenitrothion 

and aminocarb), the technology of aerial spraying, the 

development of less hazardous formulations, and the 

quantitation of off-target drift of aerosolized insecticides 

(108). These studies culminated in improvements in 

pesticide application and the establishment of regulations 

on safety or buffer zones around human habitation for 

certain types of aircraft applying different formulations 

of the insecticides. 

2.3 Multi-Agricultural Chemicals and Organic 

Solvents/Surfactants 

There is a potential for aerial applicators, associated 

personnel, and aircraft accident investigators to be exposed 

to multiple agricultural chemicals and solvents/surfactants 

of their commercial preparations for sprays, if safety and 

precautionary measures were not properly taken. Such 

poisonings could be attributed to the resultant of, and/or 

interactive effects of, each of the chemicals and solvents/

surfactants. Toxic effects of mixtures of parathion (5 

mg·kg−1), toxaphene (50 mg·kg−1), and/or dichlorophenoxyacetic acid (2,4-D; 50 mg·kg−1) for up to 7- and 14-d 

treatments in mice were determined to be the resultant 

of the effects exhibited by their components individually 

(162). Metabolic aspects of these 3 chemicals suggest 

that the toxicity of the parathion plus toxaphene mixture 

would be lower than that of parathion, as toxaphene has 

the ability to increase the biotransformation of parathion, 

as well as of paraoxon, and the levels of aliesterase, thereby 

providing a pool of non-critical enzymes for the binding of 

paraoxon (61). Because of these properties of toxaphene, 

it is anticipated that the toxicity of the parathion plus 

toxaphene plus 2,4-D mixture would also be lower than 

that of parathion (61). Chronic studies on the mixtures 

of 3 herbicides—alachlor, atrazine, and/or picloram—in 

mice suggest that the mixtures may cause hepatotoxicity 

and stimulate the liver xenobiotic-metabolizing enzymes 

(51). A chronic toxicological evaluation of mixtures of 

10 widely used pesticides—alachlor, aldrin, atrazine, 

2,4-D, DDT, dieldrin, endosulfan, lindane, parathion, 

and toxaphene—in mice revealed that these mixtures 

induce the xenobiotic-metabolizing enzymes in liver. 

Therefore, exposures to the pesticidal mixtures might 

cause deleterious effects in other species, including 

humans, by enhancing the metabolism of xenobiotics 

(52). In multi-chemical exposures, interactive effects 

among those chemicals play a contributory role towards 

associated poisonings. This type of poisoning could be 

exemplified in a multi-chemical death involving caffeine, 

nicotine, and malathion (62) and in a death attributed 

to ingestion of malathion insect spray (66). In the later 

case, in vitro inhibition of cholinesterases and presence of 

xylenes and other volatiles in certain postmortem samples 

were demonstrated (66). Therefore, these organic solvents 

may not only interact with other mixture-chemicals, but 

may also exhibit their own toxic effects. Ethylbenzene, 

a major component of mixed xylenes used as solvents in 

agriculture insecticide sprays, has been found to increase 

incidences of renal tubule, alveolar/bronchiolar, and hepatocellular neoplasms and of testicular and renal tubule 

adenomas in rats (278). Increased incidences of renal 

tubule hyperplasia, of alveolar epithelial metaplasia, and 

of severe nephropathy have been reported in rats exposed 

to ethylbenzene. The herbicide glyphosate, though it does 

not bioaccumulate, biomagnify, or persist in a biologically available form in the environment and is nontoxic 

to animals, may be formulated with surfactants (261). 

Such formulations increase the efficacy of the herbicide 

but, in some cases, are more toxic to aquatic organisms 

than the parent material. Some risks were observed for 

measured concentrations of glyphosate in surface waters 

resulting from aerial application of a formulation equivalent to Roundup to forestry areas in Canada. 
2.4 Application Safety

Aviation authorities have been concerned about the 

toxic effects of agricultural chemicals on agriculture 

pilots. In the former Soviet Union, aerial applicators 

are required to maintain records of the chemicals used 

for crop spraying and its duration (89). In the United 

States, toxicological problems in aerial application were 

recognized in early 1960s, and a considerable amount of 

applied studies were conducted at the U.S. Department of 

Transportation Federal Aviation Administration’s (FAA’s) 

Civil Aerospace Medical Institute (CAMI) in Oklahoma 

City, OK, to enhance the safety of agricultural pilots and 

their support personnel. The studies conducted at CAMI 

are summarized in Table I.

2.5 Exposure Monitoring

The health risk of aerial spraying is well known for 

pilots and ground maintenance workers. Therefore, such 

agricultural workers in the aerial spraying industry must 

be placed on occupational surveillance programs designed 

to detect the earliest toxic exposures to these chemicals. 

Since organophosphorus compounds and carbamates 

inhibit acetylcholinesterase and cholinesterases, activities 

of these enzymes in red blood cells, plasma, or whole 

blood (30–50% inhibition) is measured for monitoring 

exposures to these insecticides (89, 128, 168). Examples of 

tentative maximum permissible concentrations of parent 

compounds and/or their metabolites are: (i) 0.5 mg of

p-nitrophenol per g of creatinine in urine for parathion 

and 10 mg of naphthol per g of creatinine in urine for 

carbaryl; (ii) 15 μg of dieldrin per 100 mL of blood, 2 

μg of lindane per 100 mL of blood, and 5 μg of endrin 

per 100 mL of blood; (iii) 30 μg of hexachlorobenzene 

per 100 mL of blood and/or presence of 2,4,5-trichlorophenol in urine; (iv) 0.05 mg of pentachlorophenol per 

100 mL of plasma and/or 1 mg of pentachlorophenol per 

g of creatinine in urine; and (v) detection of 2,4-D and 

2,3,5-trichlorophenoxyacetic acid in urine (168). 

3 AVIATION COMBUSTION 

TOXICOLOGY

3.1 Combustion, Fire, and Smoke

Combustion is a rapid exothermic chemical chain 

reaction between a fuel and oxygen (air) (167, 189, 259, 

264). Heat, fuel, oxygen, and chemical reaction are necessary components for the development of a fire. Fire is a 

complex, dynamic, and physicochemical process and is 

the result of a rapid chemical reaction generating smoke, 

heat, flame, and light. Smoke consists of particulate matters, as well as a variety of invisible combustion gases and 

vapors suspended in the fire atmosphere. In other words, 

smoke is a colloidal solution consisting of gases, volatiles, 

semi-volatiles, water vapors and droplets, solid particles, 

and irritants. The involvement of particles and irritants in 

obscuring vision and in causing eye irritation, including 

respiratory irritation, cannot be ignored. Thus, combustion of burnable materials generates various products in 

smoke and it may diminish light and obscure vision, and 

its gases could be toxic (53, 63, 64, 236). 

Uncontrolled fires threaten residential and commercial 

structures and transportation systems, including aerospace 

travel. Modern aircraft benefit from fire retardants and 

fire extinguishing systems to such an extent that in-flight 

fires are rare. However, survivable crashes followed by fire 

do occur, primarily from fuel spills around the aircraft. 

Although the cabin occupants may survive the initial 

forces of such crashes, they are frequently unable to escape from the fire environment because of performance 

impairment from smoke-caused toxicity (236). Post-crash 

fire is considered to be the most important determinant 

of pilot fatalities in commuter aircraft/air taxi crashes 

(177). According to a study by the International Cabin 

Water Spray Research Management Group, there were 95 

fire-related civil passenger aircraft accidents world-wide 

over a 26-yr period (32). Fire claimed approximately 

2,400 lives in those accidents. A U.S. General Accounting 

Office publication reveals that 32 (approximately 16%) 

U.S. transport aircraft accidents between 1985 and 1991 

involved fire, and 140 (22%) fatalities in these accidents 

resulted from the effects of fire and smoke (126). During 

1991–1998, postmortem samples from 3,857 fatalities 

of 2,837 aviation accidents were received by CAMI for 

toxicological evaluation. Of these accidents, 1,012—encompassing 1,571 (41%) fatalities—were fire associated 

(67, 68). The deaths of the 3 Apollo 1 crewmembers in 

the 1967 fire accident was due to their exposure to toxic 

combustion products (276), and the involvement of fire 

has been documented in the 23 February 1997 accident 

on the Mir aerospace station (289). In this aerospace accident, the fire burned for approximately 90 s. The crew 

was exposed to heavy smoke for 5 to 7 min and donned 

their masks in response. Subsequent medical examination 

revealed that all crewmembers were in good health. 

3.2 Smoke Gases and Toxicity

Depending upon the chemical characteristics of 

burning materials and environmental conditions, such 

as temperature and oxygen content, the amounts of 

smoke products, gases, and other volatiles generated 

varies from fire to fire (123, 212). Every fire is different. 

Smoke composition and its toxicity can change drastically when different materials are present in a combustion 

environment and can be further altered by the presence 

of fire retardants and pigments. A material burned under 

one condition could be nontoxic, but it could be toxic 
Table I. Summarization of Aerial Application-Related Studies Conducted at CAMI 

Agent(s) or Topic Summary Reference Lindane and dieldrin Alterations in several biochemical values of rat tissues by chronic exposures to lindane 

and changes in the uptake of L-methionine by chick heart and liver cells by chronic exposure to dieldrin 

Daugherty et al. (93) 

Analysis of hazards in the aerial application 

Discussion on the nature of the chemicals, the symptoms of toxicity, recommended treatment, and suggestions for safe-handling of toxic pest-control chemicals 

Smith (254) 

Cardiovascular effects of endrin Causation of bradycardia, hypertension, salivation, hyper-excitability, tonic-clonic 

convulsions, increased body temperature, leukocytosis, and decreased blood pH by endrin, appeared to be caused by direct action on the central nervous system 

Emerson et al. (111) 

Dieldrin, lindane, heptachlor, isodrin, and endrin

Reduction in the esterification of inorganic phosphate by 50%, without affecting lactic acid production in chickens and rats exposed to dieldrin, but no such reduction in esterification by other chlorinated pesticides lindane, heptachlor, isodrin, and endrin 

Daugherty et al. (94) 

Cases involving aerial application of organophosphorus insecticides 

Signs/symptoms of anxiety, uneasiness, depression, weeping, dizziness, emotional liability, disagreement with family/coworkers, and unable to perform familiar tasks 

Dille and Smith (100) 

Chronic and acute effects of endrin on renal function 

Systemic hypertension and increased renal vascular resistance in dogs by acute exposure to endrin, attributed to a sympatho-adrenal action Development of progressive systemic hypotension with variable changes in renal function and terminal renal vasodilatation in dogs chronically exposed to endrin Note: These findings were related to hemodynamic alterations in the peripheral vasculature. No evidence of renal failure was observed due to chronic insecticide poisoning. 

Reins et al. (223) 

Pathological effects of endrin and dieldrin More severe effects of dieldrin on the cold-adapted rats than on the room-temperature 

rats

Clark (72) 

Effects of endrin and carbon tetrachloride Reversible increase in hepatic fat contents of rats treated with endrin and carbon 

tetrachloride 

Clark (71) 

Effects of endrin on renal function and hemodynamics, peripheral vascular system, venous return and catecholamine release, and the cardiovascular system 

Exploration of the effects of endrin in dogs on renal function and hemodynamics, peripheral vascular system, venous return and catecholamine release, and the cardiovascular system; and elucidation of the mechanisms of endrin-induced hemoconcentration 

Hinshaw et al. (144) 

Exposure of parathion and development of allergy towards aerial dusts 

Group discussion on protecting agriculture pilots Mohler and Harper 

(191) 

Human factors in general aviation accidents

Discussion on the role of medical conditions and pesticides in aviation accidents Dille and Morris (98, 

99) 
Cholinesterase measurement Development of an automated method for measuring cholinesterase activity in blood 

and tissues of animals poisoned with organophosphates and carbamates 

Fowler and McKenzie (120) 

Drug and toxic hazards in general aviation 

Summary of aerial application related precautions, signs and symptoms of pesticide poisoning, and their treatments 

Dillie and Mohler (97) 

Effects of disulfoton Increase in performance in rats given disulfoton at 10, 25, and 50 ppm in diet and 

water ad libitum and inhibition of brain acetylcholinesterase by more than 75% of 

normal in the most severely exposed group 

Pearson et al. (211) 

Human blood cholinesterase Decrease of only 10% of the original cholinesterase activity upon storage of red cell 

hemolysates for less than 12 h at room temperature, up to 3 d at 4°C, and up to 6 wk at –20°C Note: Whole blood hemolysates and plasma may be stored for 6 d at room temperature and 6 wk, if refrigerated or frozen. 

Crane et al. (78) 

Cholinesterase methods Comparison of 3 cholinesterase methods 

Importance of cholinesterase tests in applicators prior to the aerial application season 

Crane et al. (77) 

Effects of endrin on brain Brain bioelectric phenomena caused by endrin at doses well below those causing 

seizures or other gross behavioral changes Seizures in squirrel monkeys by chronic administration of this pesticide Reoccurrence of seizures some months after the termination of endrin administration, under stressful conditions, suggesting that this phenomenon may have been caused by a stress-induced release of endrin from adipose tissue storage sites Discussion on some implications of these findings for aerial applicators 

Revzin (225) 

Disulfoton Adverse effects on the reproduction system in rats by disulfoton 

Note: The number of pregnancies was decreased in the animals receiving this pesticide. Such decrease could have been attributed to such factors as alteration in the estrus cycles, the receptivity of the female animals, and decrease in sperm concentration or viability. 

Ryan et al. (231) 

Serum or plasma cholinesterase methods Evaluation of 4 serum or plasma cholinesterase methods and relationships for interconversion among their respective units 

Emphasis on the importance of the cholinesterase test in applicators prior to the aerial application season 

Crane et al. (79) 

Table I (continued)
Effects on performance of pigeons and 

monkeys of phosdrin (mevinphos), a cholinesterase inhibitor 

A dose related decrease in response rate with the animals and decrements in behavior at doses below which external symptoms of phosdrin poisoning occurred 

Lewis et al. (171) 

Mevinphos (phosdrin) Inhibition of the amplitude of hippocampal-evoked potentials in squirrel monkeys by 

mevinphos (phosdrin) in the dose range of 0.05–0.2 mg·kgí1, with no peripheral signs 

of poisoning such as tremor and salivation Emphasis that mevinphos produces changes in brain function in the absence of the peripheral symptomatology usually taken as indicators of poisoning by aerial applicator personnel Conclusion that exposure to mevinphos may be unexpectedly hazardous since the aerial applicators may be unaware that they have been poisoned 

Revzin (226) 

Mevinphos poisoning with atropine Based upon squirrel monkey experiments, potentially hazardous dysfunctions of visual 

perception in aerial applicator personnel being treated for mevinphos poisoning with atropine 

Revzin (227) 

Toxicological findings in fatal civil aviation accidents (1968–1974) 

Blood cholinesterase activity below the lower limit of the normal range in 44 of the 104 aerial applicator pilots 

Lacefield et al. (165) 

Chlordimeform Little or no extra risk in aerial applicators (or others) should they be taking pchlorophenylalanine, DL-Į-methyl-p-tyrosine, phentolamine, methysergide, and 

phenylephrine during potential exposure to chlordimeform 

Smith et al. (256) 

Toxicological evaluation of postmortem samples from 174 pilots killed in aerial application accidents 

Incidence of alcohol in specimens similar for agriculture pilots and other general aviation pilots, but the alcohol blood levels tended to be lower in the former category of pilots Evidence of the use of drugs or medications less in agriculture pilots than in other general aviation pilots Cholinesterase levels below normal in the agriculture pilots, suggesting a continuing problem of acute and/or chronic toxicity from pesticides applied by agricultural aircraft

Lacefield et al. (166) 

Table I (continued)
when burned under a different condition (86, 123)—for 

example, cotton upon burning under low-oxygen smoldering conditions produces primarily carbon monoxide 

(CO) but the much less toxic carbon dioxide (CO2

) under 

flaming conditions. Nylons tend to break down into their 

relatively nontoxic monomers at low temperatures and 

produce toxic hydrogen cyanide (HCN) when flaming. 

Fire retardants decrease flammability, but they may also 

enhance smoke toxicity (123, 212). Smoke toxicity of a 

fire retardant-treated polymer was found to be considerably higher than that of the non-treated polymer, as it 

was determined that the smoke contained a very toxic 

bicyclic phosphate (212). Most cabin furnishings contain 

carbon and will produce CO when burned, but silk, wool, 

and many nitrogen-containing synthetics are common 

sources of HCN in fires (123). Carbon-containing materials generate CO, and nitrogen-containing materials also 

generate HCN (53, 64, 113, 123, 138, 244). Benzene 

vapors and aromaticity-associated black soot would be 

produced from the burning of phenyl group-containing 

polymers, whereas hydrogen chloride from chlorinecontaining polymers (Table II). Irritants, hydrogen 

chloride and acrolein (CH2

CHCHO), can be produced 

from burning wiring insulation and some other cabin 

materials (76, 83, 123). Hydrogen fluoride, hydrogen 

sulfide, sulfur dioxide, and nitrogen dioxide gases have 

also been reported to be present in smoke (112, 113, 

142). Formation of these gases is associated with aircraft 

material formulations containing halogens, cyanide, sulfur, and nitrogen moieties. Smoke inhalation can cause 

dizziness and confusion, can induce irritation, tears, pain, 

and disorientation, and can produce incapacitation and 

death. It can also cause delayed toxicological/pathological 

effects, which could be reversible or irreversible. 

Oxygen, CO2, and CO can easily be analyzed in a 

smoke environment sample by gas chromatography, but 

the acid gases, like hydrogen cyanide and hydrogen chloride, are not so easily analyzable. Their analyses require 

additional steps and precautions because of their high 

water solubility. Therefore, they are analyzed as their 

respective anions, for example, cyanide and chloride. 

Because of incomplete oxidation, organic compounds are 

also present in smoke. Those compounds can be analyzed 

by trapping the smoke in various solvents (water, acetonitrile, and chloroform) or in carbon traps. These trapped 

organic compounds can subsequently be analyzed by gas 

chromatography/mass spectrometry, by high performance 

liquid chromatography/mass spectrometry, and/or by 

gas chromatography with a Fourier transform infrared 

or atomic emission detector. Some of these compounds 

can be characterized and confirmed if they are common 

compounds or if their reference standards are commercially 

available. Otherwise, their chemical structures can only be 

elucidated by sophisticated, analytical techniques. Some 

of the smoke compounds cannot be characterized. This 

limitation is due to the very fact that free radical chemical 

reactions are involved in the combustion process; thus, it 

becomes difficult to predict the end products. This difficulty becomes more prevalent when burning conditions 

change—for example, between smoldering and complete 

burning—and when fire retardants, preservatives, and/or 

stabilizers are present in the material being evaluated.

Phosphorus present in synthetic materials may add an 

extra variable. Because of the analytical limitations and 

the unknown toxicity of all the compounds in smoke, 

animal models have been used to determine its overall 

total toxicity. This approach integrates possible interactions among the smoke components and is able to demonstrate the net toxicity of all components. Otherwise, 

Table II. Combustion Gases From Polymersa

Polymers Chemical Unit Constituent Combustion 

Gases

Polyethylene (–CH2CH2–)n CO, CO2

Nylon 6/6 [–NH(CH2)6NHCO(CH2)4CO–]n CO, HCN, CO2

Polyamide [–NH(CH2)nNHCO(CH2)nCO–]n CO, HCN, CO2

Polystyrene [–CH2CH(C6H5)–]n CO, C6H6

b

,CO2

Chlorinated polyethylene (–CH2CH2–)n; (Cl = 40%) CO, HClb

, CO2

Polysulfone [–C6H4–4–C(CH3)2C6H4–4–OC6H4–4–SO2C6H4–4–O–]n CO, SO2

b

, CO2

a

Sanders et al. (243, 244); Fenner (119); Harper (135). 

b

Benzene (C6H6); Hydrogen chloride (HCl); Sulphur dioxide (SO2).
their contributions to the overall toxicity could not be 

evaluated. Although structures of compounds can currently be elucidated by modern sophisticated chemical 

and analytical techniques, an animal model is still an 

excellent and valid scientific approach to integrate the 

overall toxicity of smoke.

3.3 Aircraft Material Testing

The presence of cyanide in blood specimens of the 

victims of the 1970 Capitol International Airways DC-8 

post-crash fire accident at Anchorage, AK, necessitated 

the research into the origin of cyanide in aircraft fires 

(204, 235). At that time, not much was known about the 

potential for aircraft interior materials to produce toxic 

combustion gases, even about the toxicity of individual 

combustion gases. Using a small-animal test system, 75 

aircraft interior materials—panels, panel components, 

foams, fabrics, coated fabrics, floorings, thermoplastics, 

cargo liners, transparencies, insulations, and elastomers—

were ranked for their toxicity based upon the relative 

time-to-incapacitation (ti

) and time-to-death (td) caused 

by the inhalation of thermal degradation of the interior 

materials in rats (88). The former is a realistic parameter 

for estimating escape time from fire environments, and 

the latter is a parameter for finding out delayed adverse 

effects after exposure to smoke. These 75 polymeric materials were thermally decomposed using an isothermal 

heating regimen at 600o

C, though the decomposition 

method may not necessarily represent the actual processes 

occurring in a “true” fire. Toxic potentials of 14 insulating 

materials in rats with respect to response times were tested 

under 3 burning conditions (76). These conditions were 

low-temperature, non-flaming; low-temperature flaming 

with hot-wire ignition; and high-temperature, flaming at 

750oC, with or without ignition. Naturally, there were 

differences in response times at different combustion 

conditions. Based upon the findings, it was proposed that 

materials should be tested at several conditions, and they 

should be ranked based upon the most toxic-response 

time observed. 

Relative toxicity of 2 aircraft seat fire-blocking layer 

materials (Norfab and Vonar), designed to delay the 

involvement of thermally sensitive polyurethane foam 

seat cushions in an aircraft fire, was established for their 

gaseous combustion products (239). Each material was 

thermally decomposed under 5 thermal environments—2 

contact temperatures (600oC and 750oC) in a horizontal hot tube furnace and 3 flux levels (2.5, 5.0, and 7.5 

W·cm−2) in a radiant heat furnace. Rats were exposed to 

the produced combustion products in an animal exposure 

chamber with a cage, and the toxicological end point (ti

) 

was recorded when the rats could no longer perform the 

coordinated act of walking in the rotating cage (when 

sliding or tumbling began). In 3 of the 5 test environments, the gaseous products of Norfab (an aluminized 

synthetic fabric) produced shorter ti

s than those by the 

products of Vonar (a neoprene foam product). HCN 

was detected in the combustion products of Norfab but 

not in the combustion products of Vonar. The greater 

apparent toxicity of Norfab was possibly because of HCN. 

Additional studies that ranked 9 flat panel materials based 

upon their combustion products in rats suggested that 

only the higher temperatures in both the combustion 

tube and radiant heat systems proved to be suitable for 

toxicological differentiation between the panels. The 

shortest tis occurred at the highest temperature/heat flux 

condition for both chambers (86). A comparative toxicity 

study involving rankings of 6 polymeric aircraft cabin 

materials—polyamide (I), polystyrene (II), Nylon 6/6 

(III), polysulfone (IV), polyethylene (V), and chlorinated 

polyethylene (VI)—was conducted in rats (243, 244). 

Animals were exposed to the pyrolysis products from 

selected weights of each polymer for 30 min in a 265-L 

combustion/exposure system. The LC50s were determined 

following a 14-d observation period. The ti

s were also 

measured at 16 g (60 mg·l−1) and at their respective LC50s 

using the inability of rats to walk in rotating cages as a 

criterion for incapacitation. The LC50s (mg·l−1) of the 

polymers had the order of I (45.7) < II (56.6) ≈ III (58.1) 

< IV (63.2) < V (75.5) < VI (87.5), while their ti

s (min) 

at 16 g (60 mg·l−1) had the order of III (6.6) ≈ I (7.3) < 

V (11.7) ≈ II (12.0) < VI (18.4) < IV (21.1). Based on 

the tis at LC50s, the polymers were grouped into III and 

V (10.5, 11.0); I, II, and VI (14.1-15.0); and IV (19.5). 

These 2 endpoints did not exhibit the same relative toxic 

hazard rankings for these polymers. Also, ti

s were not 

equal at the LC50 concentrations, a condition of equal 

lethality, demonstrating the possible involvement of different mechanisms of action for the combustion products 

of these polymers at the selected end points. In spite of 

experimental limitations, toxicity ranking of aircraft 

materials has applicability in minimizing the toxicity of 

smoke and the spreading of fires.

3.4 Gases and Their Interactive Effects

3.4.1 Gas Interactions

Since aircraft materials, upon combustion, have the 

potential for generating hydrogen halides (hydrogen 

fluoride and hydrogen chloride), HCN, and nitrogen 

dioxide (142), experiments were conducted with rats to 

determine toxic effects (lethality) of short-term exposures 

to these gases. These experiments were conducted both 

with single gases and in combination with CO. These 

studies show the toxicity rankings of the 4 products to be 

HCN > nitrogen dioxide > hydrogen fluoride > hydrogen 

chloride. CO concentrations, which alone are not hazard-
ous, do not enhance the toxic response to these gases. 

Effects of hydrogen chloride inhalation have been studied 

on ti and td in rats (85). These 2 endpoints were equated 

to the atmospheric hydrogen chloride concentration by 

statistically derived regression equations, and the possible 

relationship was discussed between the effective toxic 

doses of this gas for rats and those reported for humans. 

Toxicological evaluation of another irritant acrolein—a 

combustion product of certain materials used in aircraft 

interiors—in rats indicated that concentrations required 

to produce incapacitation were 100 times greater than 

those suggested by the scientific literature; equations were 

derived to allow prediction of ti

 and td for the laboratory 

rat (87). The possible relationship between the effective 

toxic doses of acrolein for rats, and those reported for 

humans, was also discussed. 

Influence of elevated temperatures—ambient versus 

elevated temperatures from 40 to 60°C—on the effects 

of CO-induced ti

s in rats were studied as a function of 

CO concentration and/or temperature in an exposure 

chamber (240-242). The combined CO plus elevated 

temperature exposures and exposures to CO and elevated 

temperatures (40–60oC) alone indicated that incapacitation occurred earlier when CO inhalation was combined 

with a whole-body, elevated temperature environment 

than that was observed for the same exposure parameters 

applied individually. An empirical equation was derived 

that allows calculating a predicted ti

 for combinations of 

CO and temperature.

Further interactive studies on CO and acrolein by 

exposures of rats to experimental atmospheres of CO in 

air, acrolein in air, and mixtures of CO and acrolein in 

air and the measurement of ti indicated no evidence of 

synergistic action, since the effect of the combination 

was never greater than that predicted by the sum of the 2 

individual gas effects (81, 82). However, evidence did exist 

for an inhibitory or antagonistic effect of an undefined 

mechanism when acrolein was present in the mixture 

at concentrations of lesser toxic potency than that of 

CO. Equations were derived that allows the calculation 

of a predicted ti for combinations of CO and acrolein 

concentrations. 

Evaluation of the toxic potencies of CO, HCN, and 

their mixtures by the measurement of ti in rats as a function of gas concentrations indicated that the 2 gases are 

fractionally additive (80), with no indication of synergism—wherein the effect of the combination would have 

been greater than that predicted from the sum of the 2 

individual effects. Regression equations were derived that 

describe those relationships for exposure to CO or HCN 

alone. An empirical equation was derived that allows 

calculation of the predicted ti

 for any combination of CO 

and HCN concentrations. A dose-response modeling, 

based upon the concept of “Fractional Effective Dose” 

(see next section), was used to devise a mathematical 

model for estimating ti

 produced by defined mixtures 

of CO and HCN. 

3.4.2 Fractional Effective Dose (FED)

The average concentration of a gas to which an animal 

was exposed is calculated from the area under the gas 

concentration (C)-exposure time (t) curve integrated from 

t = 0 to t = t

i

, representing the C∙ti product (80). The C∙t

product for a gaseous toxicant is expressed in a volume 

fraction of μl·l

−1 (parts per million; ppm) multiplied by 

minutes. Division of this product by ti

 yields the average effective exposure concentration (CAEE) of the gas to 

which the animal was exposed, causing incapacitation 

(Equation 1).

 

(1)

FED is a ratio of the C∙t product for a gas to that product 

of the gas expected to produce a given effect, such as ti

, on 

an exposed subject, such as a rat, of average susceptibility 

(65, 80, 139, 237, 263). When not used with reference 

to a specific gas, the term FED represents the summation of FEDs for all gases in a combustion atmosphere. 

As a concept, FED may refer to any toxicological effect, 

including incapacitation or lethality. The FED of each 

gas in a mixture is calculated by dividing the C∙t value 

of the gas in the mixture by the corresponding C∙t value 

for exposure to the same gas alone for any effect such as 

t

i

 or td. For an additive effect of 2 gases in their mixture, 

at time t, into exposure: 

FEDGas1,t + FEDGas2,t =1 (2)

FED is a function of time. The effect occurs when the 

FED reaches unity. Therefore, to be an additive effect, the 

reciprocal of the ti

 value for the combined gases should 

be equal to the sum of the reciprocal ti

 values observed 

with the individual gases, as

Such an FED-based model has been suggested to be 

applied to the evaluation of the toxicity of smoke in 

computer modeling of aircraft fire situations (263). To be 

used as a predictive tool to estimate human survivability 

in full-scale aircraft cabin fire tests, this model included 

literature data for CO2

, low oxygen, CO, HCN, hydrogen 

fluoride, hydrogen chloride, hydrogen bromide, nitrogen 

dioxide, sulphur dioxide, acrolein, and heat exposures 

and was based on exposures to single and mixed gases 

on humans, primates, rats, and mice at different physical 

activity levels. In this model, FEDs were obtained for 

i

i

i

t t

t

AEE t

C t

t

Cdt

C

i

× = = ∫

=

=0

( ) ( ) ( )

1 1 1

i CO HCN i CO i HCN t t t = ++ (3)
10

incapacitation and for lethality, and the exposure time 

required for either FED to reach unity represented the 

exposure time available to escape from the specified fire 

environment or to survive post-exposure. The effect of 

CO2 in increasing the uptake of other gases was factored 

into the concentration term in the FED equation for all 

gases, with the exception of CO2

 and oxygen. In this 

regard, higher respiratory minute volumes, because of 

CO2 exposure, were found to be an important factor 

in predicting the time available to escape. Computer 

modeling of human behavior in aircraft fire accidents, 

including toxicity sub-model through the FED calculations, has been elaborated (124).

3.4.3 Carboxyhemoglobin (COHb) and Blood 

Cyanide Ion (CN ̄) 

It is well-established that carbon-containing substances 

generate CO upon burning, whereas nitrogen-contain-

ing substances also produce HCN (53, 64, 113, 123, 

138, 244). These chemical species are 2 primary toxic 

combustion gases and are present in relatively high concentrations in smoke. Both gases are present in the blood 

of fire victims (18, 68, 170, 183, 185, 253, 290). Since 

both gases have adverse effects on the central nervous 

system functions (129, 158, 258), excluding burn and 

physical injuries, the primary cause of incapacitation or 

death is attributed to exposures to these 2 gases. Other 

smoke constituents may also be toxic, but they are generally present at low concentrations, thus are unable to 

produce a considerable degree of the acute undesired 

effects. However, they may have the potential to produce 

delayed toxic effects, depending upon the duration and 

frequency of exposure to those products and their chemical 

structures. The hydrocarbon constituents of smoke have 

the capability of adversely affecting the central nervous 

system functions, as well. 

Since aircraft materials do contain carbon and nitrogen, they generate CO and HCN upon burning, and air 

passengers could be exposed to these gases by inhaling 

smoke in the unfortunate event of in-flight or post-crash 

fires. The actual degree of toxicity produced by smoke 

can be established in the victims of fire by the analysis of 

their blood for CO as COHb and HCN as CN ̄. Various 

analytical methods for the blood analysis of COHb and 

CN ̄ are summarized in Tables III and IV. 

Although much research has been conducted in establishing the relationship between CO and/or HCN 

exposure doses and toxicological responses, there has been 

sparsity in examining the relationship between blood 

concentrations of COHb and/or CN ̄ and a toxicological 

response. In view of the suggestion that passenger protective breathing equipment protect aircraft passengers from 

smoke for 5 min during an evacuation phase and for 35 

min during an in-flight-plus-evacuation phase (114), ti

was determined at 2 CO concentrations that produce 

5- and 35-min ti

s in rats (245). Also, blood COHb 

saturation was determined in rats exposed to these CO 

concentrations at intervals less than ti

. At the end of each 

exposure interval and at incapacitation, rats were quickly 

removed from the cage and killed for blood collection and 

COHb quantitation. The observed reaching of COHb to 

a maximal level before incapacitation suggests that blood 

COHb saturation levels may not necessarily be indicative 

of the onset of incapacitation. In similar experiments with 

HCN, ti and blood CN ̄ at ti for 2 HCN concentrations 

that produce 5- and 35 min ti

s were determined in rats 

(60). Blood CN ̄ levels as a function of HCN exposure 

time were also measured. Blood CN ̄ levels increased as 

a function of HCN exposure time, but the blood CN ̄

level at the 5-min ti was half of the 35-min blood CN ̄ 

level, and the HCN gas uptake rate at 184 ppm was 

about 3 times that at 64 ppm. Findings suggested that the 

blood CN ̄ level at incapacitation may vary substantially, 

depending upon the HCN exposure concentration. An 

equation was proposed for predicting blood CN ̄ levels 

in rats (Equation 4).

 (4)

where 

Ccn-is blood CN ̄ concentration in μg·ml−1;

Chcn is HCN exposure concentration in ppm;

t is exposure time in min; and

K is a constant with the value of 2.2 × 10 –3.

3.4.4 COHb and Blood CN ̄ Interactive Effects

Exposures to CO-HCN mixtures have demonstrated 

that these gases have additive effects, that is, shorter ti

s 

(Equation 3), but the resulting concentrations of COHb 

and blood CN ̄ at incapacitation are not well defined. 

These undefined relationships between COHb and blood 

CN ̄ concentrations and the onset of incapacitation make 

the interpretation of postmortem levels difficult for medical accident investigators. Therefore, ti

 was determined in 

laboratory rats exposed to 2 CO-HCN mixtures consist-

ing of CO and HCN concentrations that produce 5- and 

35-min ti

s in individual gas exposures (65, 237). In the 

high concentration CO-HCN mixture, the resultant ti

 was 

shortened from 5 min to 2.6 min; COHb dropped from 

81% to 55% and CN ̄ from 2.3 μg·ml−1 to 1.1 μg·ml−1. 

At the lower concentration CO-HCN mixture, where the 

resultant ti reduced from 35 min to 11.1 min, COHb 

dropped from 71% to 61%, and blood CN ̄ decreased 

from 4.2 μg·ml–1 to 1.1 μg·ml–1. 

Both the C∙t-based FED model and ti calculations from 

Equations 2 and 3 indicated that CO and HCN have 

additive effects on ti

 at high concentrations and could 

(CCN ̄ )÷ (CHCN ×t)= K
11

Table III. Analytical Methods for Determining COHb Concentrations in Blood Method Principle, Sensitivity, and Limitation Reference Whole-blood oximetry Simultaneous automated differential visible spectrometry at various characteristic wavelengths. 

COHb as low as 10% in fresh blood from live victims (accuracy: 1í2%). Suitable for fresh heparinized blood and maybe unsuitable for putrid or clotted blood. Note: Ethylenediaminetetraacetate (EDTA) could be used with CO-Oximeter (74). Citrate, fluoride, oxalate, and EDTA cause errors with AVOXimeter (7). 

Freireich et al. (121); COOximeter (74); AVOXimeter (7) 

Palladium chloride reduction 

Release of CO from COHb by sulfuric acid added to blood in the outer rim of a Conway cell, reduction of palladium chloride in the centre well of the cell to palladium, and measurement of absorbance at 278 nm of the remaining unreacted palladium chloride solution in the centre well and of a new aliquot of the palladium chloride solution. Unable to measure COHb below 10% (coefficient of variation: ± 5.2%), could be used for analyzing fresh or uncoagulated antemortem or postmortem blood. Note: COHb saturation can be calculated by determining the concentration of total hemoglobin in blood (7, 74, 110, 115). Presence of a shiny black film of palladium on the palladium chloride solution may suggest presence of COHb > 30%. Putrid blood may not be suitable for analysis. Sulfides present in 

putrid blood in large concentrations interfere with analysis, but such interference can be rectified by using a saturated lead acetate-acetic acid solution in place of sulfuric acid as the CO releasing reagent. 

Williams et al. (297); Williams (295, 296) 

Visiblespectrophotometry (calibration curve) 

Hemolysis of red blood cells by ammonium hydroxide, treatment of the hemolysate by sodium dithionite to reduce methemoglobin (MetHb) and oxyhemoglobin (OxyHb) to deoxyhemoglobin (HHb), and measurement of the absorbance at 540 nm, a wavelength of maximum absorbance for COHb, and at 579 nm, a wavelength at which the spectra of various species of HHb have the same absorbance (isobestic point). Note: A ratio of absorbance values at 540 nm and 579 nm is used to determine % COHb in the specimen from a calibration curve. Accurate estimation of COHb  10%, suitable for fresh or un-coagulated antemortem or postmortem blood, but unsuitable for putrid blood as resulting pigments can distort COHb and HHb spectra 

Winek and Prex (298); Douglas (104); Tietz and Fiereck (272); Blanke (25);Sanderson et al. (246); Canfield et al. (43, 44) 

Visiblespectrophotometry (CO saturation) 

Saturation of Part 1 of the 3 parts of blood hemolysate with CO and of Part 2 with oxygen (no treatment of Part 3 with any gas), addition of sodium dithionite to all the 3 parts to reduce MetHb and OxyHb to HHb, and determinations of ratios of the absorbance values of the solutions at 540 nm and 579 nm to find out % COHb in the specimen by using a mathematical relationship capable of accurately measuring  10% COHb in fresh and postmortem blood stored with sodium fluoride and potassium oxalate. Note: Clotted blood may be used after homogenization, but old or putrid blood may interfere with analysis.

Winek and Prex (298); Sanderson et al. (246); Canfield et al. (43, 44); Rodkey et al. (230); Widdop (293); Uges (279) 
12

Visiblespectrophotometry (without CO saturation) 

Hemolysis of red cells of blood specimens, reduction of MetHb and OxyHb to HHb, and calculation of ratios of the absorbance values of the specimens at 540 nm and 579 nm. Note: Absorbance ratios are used to determine % COHb in the specimen by using a mathematical equation in relation to a positive COHb control prepared in human blood by using CO. Capable of accurately measuring  10% COHb in fresh and postmortem blood samples stored with 

sodium fluoride and potassium oxalate. (Also, see previous method.) 

Winek and Prex (298); Sanderson et al. (246); Canfield et al. (43, 44) 

Headspace gas chromatography (nickel-hydrogen reduction) 

Conversion of MetHb and OxyHb to HHb by sodium dithionite in 2 separate aliquots of blood samples; saturation of 1 aliquot with CO (no CO treatment of the second aliquot); release of CO from both blood aliquots by a ferricyanide or phosphoric acid solution; injection of headspace air samples of the COsaturated and non-CO treated sample aliquots on a gas chromatograph equipped with a column, a methanation unit (nickel catalyst and hydrogen unit); flame ionization detection of methane; and calculation of % COHb level in a blood sample by comparing methane peaks of the CO-saturated original blood sample and of the non-CO treated blood sample. Capable of accurately determining COHb at the levels equal to or greater than 10% in fresh blood and postmortem blood samples. Note: Clotted blood can be homogenized prior to use. Putrid blood and both heparin and sodium fluoride-potassium oxalate treated blood can be used for analysis. 

Griffin (130);Cardeal et al. (45) 

Headspace gas chromatography (thermal conductivity detection) 

Separation of the submitted sample into 2 parts; treatment of both parts with sodium dithionite to reduce MetHb and OxyHb to HHb saturation of 1 part with CO (other used without CO-treatment); release of CO from the both parts by sulfuric acid with saponin; injection of headspace air samples of the COsaturated and the non-CO treated samples onto a micro-gas chromatograph; and comparison of gas chromatograph CO peaks of original blood sample (non-CO treated) and of the CO-saturated blood sample, thereby calculation of % COHb level in a blood sample. Note: For sensitivity and limitation, see previous methods. 

Endecott et al. (113);Lewis et al. (174) 

Table III. (continued)
13

Table IV. Analytical Methods for Determining CN ̄ Concentrations in BloodMethod Principle, Sensitivity, and Limitationa Reference Colorimetry (p-nitrobenzaldehyde and 

o-dinitrobenzene) 

Reaction of CN ̄ present in blood with p-nitrobenzaldehyde and o-dinitrobenzene under an alkaline condition and production of a violet color, suggesting the presence of a potentially toxic CN ̄ concentration, a quick qualitative method. Detectable minimum CN ̄ concentration by directly using the specimen: 0.3 μg·mlí1 and by 

diffusion: 0.05 μg·mlí1

Rieders (229); Guilbault and Kramer (131); Dunn and Siek (105) 

Visible spectrophotometry Liberation of HCN from blood by acidification and microdiffusion, trapping of HCN in a dilute 

alkaline solution, and conversion of HCN to cyanogen chloride after reacting with chloramine-T. Subsequent reaction between cyanogen chloride and pyridine to form N-cyanopyridinium chloride, 

followed by a cleavage reaction to form an anil of glutaconic aldehydes and, then, coupling with barbituric acid to generate a red-pinkish, highly resonant product, suggesting presence of CN ̄. 

Note: A CN ̄ concentration of as low as 0.25 μg·mlí1 can be easily detected by processing 0.5 ml of 

blood specimen. Blood or tissues containing formalin cannot be analyzed, as formaldehyde reacts 

with CN ̄ to form cyanohydrin, which is quickly converted into ammonia and glycolic acid. 

Feldstein and Klendshoj (117); Rieders (228); Blanke (24) 

Headspace gas chromatography (nitrogenphosphorous detection) 

Equilibration of blood in the presence of acetonitrile as an internal standard in a vial at room temperature for 30 min and injection of the headspace of the vial onto a gas chromatograph equipped with a nitrogen phosphorus detector to detect HCN and acetonitrile. Linearity: 0.25–15 μg·mlí1; sensitivity: 0.05 μg·mlí1

Zamecnik and Tam (302); McAuley and Reive (186) 

Headspace gas chromatography (electron capture detection) 

Liberation of HCN from blood, chlorination of HCN to cyanogen chloride by reaction with chloramine-T, and injection of headspace onto a gas chromatograph equipped with an electron capture detector. Linearity: 0.005–1 μg·mlí1; suitable for clinical and toxicological purposes 

Odoul et al. (206) 

Spectrophotofluorimetry or high-performance liquid chromatography (fluorescence detection) 

Transformation of CN ̄ by acidification from blood to HCN, reaction of CN ̄ in HCN with 2,3-naphthalenedialdehyde and taurine in a self contained system, and fluorimetric measurement (λexcitation = 418 nm; λemission = 460 nm) of the reaction product, 1-cyano-2-benzoisoindole (1-

cyano[f]benzoisoindole; CBI) derivative. A specific method for CN ̄ with the detection limit of 0.002 μg·mlí1CN ̄; linearity: 0.002–1 

μg·mlí1 by spectrophotometric determination and 0.002–5 μg·mlí1 by HPLC determination; suitable 

for clinical and toxicological purposes 

Felscher and Wulfmeyer (118) 
14

High-performance liquid chromatography (mass spectrometric detection) 

Using isotopic potassium cyanide (K13C15N) as an internal standard, microdiffusion of CN ̄ and 

13C14N ̄ from blood as HCN and H13C14N, reaction of CN ̄ and 13C14N ̄ in HCN and H13C14N with 

2,3-naphthalenedialdehyde and taurine in a self contained system to produce non-isotopic and isotopic analogs of CBI, and qualitative and quantitative determination of both CBI analogs by high performance liquid chromatography-mass spectrometric detection. Note: The molecular weight of the isotopic CBI–13C14N derivative is more by 2 atomic mass units 

than that of non-isotopic CBI–CN derivative. This method should be suitable for clinical and toxicological purposes. A simple, rapid, and extremely specific method; detection limit: 0.005 μg·mlí1; linearity: 0.015–3 μg·mlí1

Tracqui et al. (273) 

aFresh and postmortem blood samples could be analyzed by the majority of methods included herein. Clotted blood may also be analyzed after homogenization. Other sample 

types that can be analyzed are plasma, serum, gastric content, cerebrospinal fluid, urine, and tissue homogenates. Only 33% of the unmeasurable CN ̄ could be attributed to the conversion of CN ̄ to thiocyanate (SCN ̄). Sodium thiosulfate (Na2S O2 3), the antidote for treating CN ̄ poisoning, has been reported to interfere with colorimetric, fluorimetric, 

and potentiometric methods for CN ̄ measurement (192, 267, 288). 

Table IV. (continued)
15

have other than additive effects at lower concentrations. 

The lower ti(CO + HCN) of 11.1 min in comparison to the 

calculated value 16.4 min from Equation 3 and less than 

unity value in Equation 2 could be associated with the 

limitations of the C∙t theory and its related FED concept 

(80, 156, 207). When the FED model was employed us-

ing % COHb and μg·ml–1 CN ̄ levels at incapacitation, 

the FEDs—that is, FEDCOHb + FEDHCN—were obtained 

for the high- and low-concentration mixtures of these 2 

gases. The calculated values were correspondingly 1.16 

and 1.12. In this regard, it should be realized that the 

COHb level was almost linear up to 5 min and started 

reaching a steady state before 11.1 min at the 35-min ti

CO concentration. Therefore, the FED model may have 

limitations for COHb and CN ̄ levels, except in the extremely short exposure periods when both CO and HCN 

uptakes are linear (65, 237). The evaluation of COHb 

and blood CN ̄ values with the values from the single 

gas exposure studies indicated that any alteration of the 

uptake of either gas in blood by the presence of the other 

gas was minimal. These findings suggested that changes in 

COHb and blood CN ̄ might not be directly correlated 

with the onset of incapacitation and that postmortem 

blood levels should be carefully evaluated, particularly 

when both gases are present in fire victims.

Interpretation of elevated levels of COHb and CN ̄ to 

the degree of toxicity caused by CO and HCN becomes 

challenging because both gases have interactive effects 

on the central nervous system (129, 138, 158, 258). 

When the FED concept (see Equation 2) is applicable, 

the FEDCO + FEDHCN should equal unity for an additive 

effect of CO and HCN. By employing the FED model 

using blood % COHb and μg·ml–1 CN ̄ concentrations 

in place of CO and HCN effective exposure doses, 

Equation 5 could be used to account for the additive 

effects caused by these gases (38, 39). In this equation, 

“Fractional Toxic Concentration” in blood (FTCBlood) is 

used in place of FED.

It is documented that CO at 70% COHb and HCN 

at 3.0 μg·ml–1 (μg/ml) CN ̄ would alone cause lethality 

(129, 137, 201). However, the FTC concept does not rule 

out other than additive effects of these gases. Therefore, 

the concentrations of COHb and CN ̄ in blood and 

interactive potentials of both species should be carefully 

considered when interpreting and correlating their blood 

concentrations with the toxicological effects. For example, 

the presence or absence of these species in blood would 

suggest whether the individual died after inhaling smoke 

or prior to the fire. 

3.4.5 COHb and Blood CN ̄ in Fire-Involved Aircraft 

Accident Fatalities

As mentioned earlier, occurrences of in-flight smoke 

and fire are rare in modern aircraft. However, if and when 

that happens, the consequences are deadly (2, 73, 187, 

213, 275). For instance, the involvement of an in-flight fire 

was deduced in the Swissair accident that occurred on 2 

September 1998, near Peggy’s Cove, Nova Scotia, Canada 

(275). Compared to in-flight fires, post-crash (ground) 

fires are generally more common, primarily originating 

from spilled fuel around the aircraft. In the crash of Galaxy 

Flight 203, on 21 January 1985, near Reno, Nevada, most 

victims survived the impact but succumbed to fire and 

toxic gases (234). Sixty-eight persons died at the scene, 

2 died during hospitalization, and 1 survived. Fifty-four 

people died in the British Air Tours Boeing 737 accident 

at Manchester, United Kingdom, on 22 August 1985 

(185). Fire was involved in the accident. Blood COHb 

and CN ̄ were elevated in most of the victims. Volatile 

substances were also detected in the blood of the victims 

and carbon particles in the trachea and bronchi. 

In such post-crash fires, aircraft occupants are frequently unable to escape from the fire environment because of 

physical injuries and/or performance impairment from 

smoke-induced toxicity and visual obscuration. Such 

inability leads to incapacitation and death. Therefore, it 

is common to determine COHb and blood CN ̄ concentrations in fire-associated aircraft accident fatalities to 

establish the degree of toxicity (67, 68, 185, 204). 

3.4.6 Analytical Results Interpretation

3.4.6.1 Analysis

Commonly used analytical procedures for measuring 

COHb and CN ̄ in blood are summarized in Tables 

III and IV. The blood quality could affect the accuracy 

of the concentrations of these species; therefore, it is 

an analytical and toxicological concern. From aviation 

accident fatalities, quality blood samples are frequently 

difficult to obtain. The quality of the blood is dependent 

upon the postmortem interval—that is, the time between 

death and blood collection. Old or putrid blood samples 

may interfere with the analysis. Clotted blood samples 

could be homogenized prior to analysis. Solid burned 

blood samples may not be suitable for analysis, though 

their aqueous homogenates could be analyzed. However, 

it would be difficult to interpret such analytical values. 

The blood collection technique and container, the types 

of anticoagulants and/or preservatives used, the sample 

storage conditions, the analysis time after sample collection, the ratio of surface area to volume of blood 

(5) 1  ̄ (3.0μg/mL)

 ̄ (μg/mL)

70%

% = +  ̄ = + = CNCN

COHb

COHb

FTC FTC FTC Sample Sample

Blood COHb CN
16

exposed to the atmosphere, the storage condition and 

temperature, and the initial % COHb saturation (50) 

and blood CN ̄ concentration also adversely affect the 

outcome of such analyses. 

3.4.6.2 COHb Concentrations

Although COHb below 5% is considered normal, 

healthy individuals may accumulate up to 10% COHb 

by inhaling CO-contaminated air (17, 296). COHb 

concentrations as high as 17% have been documented 

in heavy smokers (286). An approximately 20% decrease 

in COHb levels as a function of time has been reported 

in postmortem blood samples collected from fire victims 

(170). Therefore, COHb analytical values may not reflect 

the true levels of this species at the time of death, but 

they may represent approximate values at death. For a 

given % COHb concentration, effects may be more severe in physically active subjects or following prolonged 

exposures of several hours (190, 214, 215). Because of a 

considerable range of sensitivity to CO poisoning in the 

population, fatalities from CO exposures show a wide 

range of COHb concentrations, from approximately < 

30% to 95% COHb (200). Toxicity of CO poisoning 

is associated with the central nervous and cardiovascular 

systems wherein the oxygen demand is high (129, 158, 

258); COHb concentrations and associated signs and 

symptoms are given in Table V (129). 

3.4.6.3 CN ̄ Concentrations

Blood CN ̄ concentrations are also strongly affected 

by the postmortem interval, decreasing by approximately 

50% per day in a cadaver (10, 90). CN ̄ in blood can be 

in the HCN form. In its protonated form, CN ̄ as HCN 

could be easily diffused through the body and released 

into the surrounding atmosphere, thereby reducing CN ̄ 

levels. Release of HCN from cyanomethaemoglobin 

(cyano-MetHb) has been reported by heat denaturation, 

as well (252). The majority of the analytical methods measure total CN ̄ originating from both critical 

(cyanide-cytochrome oxidase complex) and non-critical 

(cyano-MetHb; erythrocytes) sites (65, 129, 158, 188, 

284). Normal human blood concentrations range from 

0.0 to 0.30 μg·ml–1 in nonsmokers and from 0.02 to 

0.50 μg·ml–1 in smokers (12, 184, 268). Originating 

from cyanogenic glycosides or pyocyaneous organisms, 

CN ̄ concentrations up to 0.15 μg·ml–1 in blood could 

be found in adults without symptoms (16, 21, 24, 29, 

91, 92, 129). A CN ̄ value of < 0.25 μg·ml–1 may not 

have toxicological relevance, as clinical manifestations are 

observed at CN ̄ concentrations of ≥ 0.5 μg·ml–1 (Table 

VI) (129), though toxic effects of CN ̄ on fire victims 

should not be solely based upon its blood concentration 

(193, 194). 

CN ̄, a rapidly acting toxic chemical entity, is capable 

of causing incapacitation quickly (129, 158, 258). As the 

CN ̄ concentration increases, unavailability of oxygen to 

the central nervous system may cause hypoxic convulsions, 

followed by death due to respiratory arrest. Inhalation 

of HCN rich smoke induces hyperventilation, thus increasing the rate of uptake until the victim collapses and 

becomes comatose. When the rate of uptake decreases, the 

victim may temporarily recover. Such recovery, however, 

may be short lived, leading into a gradual but fatal decline 

(214, 216). Although high blood CN ̄ concentrations 

probably result from the release of sequestered CN ̄ in 

the red blood cells (8, 11, 14, 15, 274, 284) and blood 

concentrations of CN ̄ could be correlated with its toxicity 

(13, 129, 188), the associated signs and symptoms may 

be more closely related to plasma CN ̄ concentrations 

than whole blood CN ̄, as an unconscious victim may 

recover quickly of the cessation of exposure without any 

decline in whole blood CN ̄ (214, 216). 

3.4.6.4 MetHb, Cyano-MetHb, and 

Sulfmethemoglobin (Sulf-MetHb)

Including CO and HCN, numerous species could be 

produced during combustion of substances (107, 113, 

123, 136, 138, 244), and some of these may be very 

reactive, thus may convert HHb to MetHb. MetHb 

may also be produced by heat (116) and by postmortem 

oxidation of HHb (157, 203, 247). Smoke rich in HCN, 

hydrogen sulfide, or sulfur-containing substances may 

react with MetHb to form cyano-MetHb and sulf-MetHb 

(129). The latter could also be formed postmortem as 

hydrogen sulfide and sulfur species are produced during 

putrefaction. 

Sulf-MetHb interferes with spectrophotometric analytical methods (74, 258), particularly when this species 

is present in high concentrations. Spectral absorbance 

of sulf-MetHb is similar to that of MetHb. Also, some 

analytical methods do not account for cyano- and sulfMetHb in measuring total hemoglobin. Therefore, % 

COHb results could be erroneously high by using those 

methods. 

During COHb measurements, sodium dithionite is 

used as a reducing agent to convert OxyHb and MetHb 

to HHb to maximize the CO binding capacity of the 

blood sample. However, it has not been clearly established 

whether such dithionite treatment would also reduce 

cyano- and sulf-MetHb to HHb, though polysulfides, 

thiosufate, and sulfate have been known to reduce sulfMetHb to HHb (129). If these HHb-analogs, as well as 

OxyHb and MetHb, could not be completely converted 

to HHb by the dithionite treatment, then the binding 

capacity of the blood sample would not be maximum, 
17

Table V. Percent COHb and Associated Sign and Symptoms (129)

% COHb Signs and Symptoms 

0–10 No symptoms 

10–20 Tightness across forehead, possible slight headache, and dilation of 

cutaneous blood vessels 

20–30 Headache and throbbing in temples, easily fatigued, and possibly 

dizziness 

30–40 Severe headache, weakness, dizziness, confusion, vision dimness, 

nausea, vomiting, and collapse 

40–50 Signs and symptoms same as above, but severity is higher; increased 

pulse and respiratory rate 

50–60 Increased respiratory and pulse rate, coma, intermittent convulsions, and 

Cheyne-Stokes respiration 

60–70 Coma, intermittent convulsions, depressed heart action and respiratory 

rate, and possible death 

70–80 Weak pulse, slow respiration, respiratory failure, and death within a few 

hours 

80–90 Death in less than an hour 

> 90 Death in a few minutes 

Table VI. Blood CN ̄ Concentrations and Associated Toxicity (129) 

Degree of Toxicity (Blood CN ̄) Signs and Symptoms 

Mild (0.5–1.0 μg·mlí1) Flushed, rapid pulse, conscious, and headache 

Moderate (1.0–2.5 μg·mlí1) Stuporous but responsive to stimuli, tachycardia, and 

tachypnea 

Severe ( 2.5 μg·mlí1

) Comatose, unresponsive, hypotension, slow 

respirations, gasping, mydriasis, cyanosis at high 

concentration, and death 
18

and thereby the observed % COHb values would be 

erroneously higher in comparison to the situation when 

these hemoglobin species would have been completely 

reduced to HHb. Therefore, cyano-MetHb and sulfMetHb at high concentrations may potentially interfere 

with the COHb analyses, thus may provide inaccurate 

analytical results.

4 POSTMORTEM AVIATION 

FORENSIC TOXICOLOGY

4.1 Introductory Comments

The field of Postmortem Aviation Forensic Toxicology falls 

between the categories of Postmortem Forensic Toxicology 

and Human-Performance Forensic Toxicology. Per their 

definitions in the forensic toxicology laboratory guidelines (260), the former deals with the cause and manner 

of death, whereas the latter with human performance 

or behavior. The flying process involves the interaction 

between man and the machine, and it is not only the 

equipment failure, but also the performance impairment and/or abnormal behavior of aviators that might 

contribute to an accident. Such accident could be fatal. 

The performance/behavior-related changes in aviators 

may be because of the presence of foreign substances in 

their system and/or of health reasons. Therefore, during 

aviation toxicology evaluation, postmortem biological 

samples from aviators are analyzed for the presence of 

foreign substances—combustion gases, ethanol/volatiles, 

and drugs—to establish whether the foreign substance(s)-

induced performance impairment/behavioral abnormality 

was the cause or a factor in a particular aviation accident 

(35, 41, 69, 262). Most of the drugs present in the 

pilot samples are in the subtherapeutic-to-therapeutic 

concentration range (6, 35, 41, 69, 250, 262), which is 

consistent with the nature of postmortem aviation toxicology and could basically be referred to as the humanperformance associated postmortem forensic toxicology 

(260). The presence of drugs would also be suggestive 

of their underlying medical conditions for which they 

were treated.

During fatal aircraft accident investigations, postmortem samples are collected from pilot fatalities and 

toxicologically evaluated in a forensic toxicology facil-

ity. The facility could be associated with a local or state 

agency in some countries, while with a federal agency 

in others. In the United States, the toxicology facility is 

located at CAMI (1, 69, 103). The sample submission 

is coordinated through the FAA’s Office of Accident 

Investigation by the National Transportation Safety 

Board. This Board is responsible for investigating all U.S. 

civilian aircraft accidents. In the majority of situations, 

the samples are from pilots and copilots. Samples from 

passengers and other crewmembers are also sometimes 

submitted, depending upon the nature of an accident—for 

example, an accident involving fire. Multiple types of 

postmortem specimens—blood, urine, vitreous fluid, 

spinal fluid, brain, lung, heart, liver, kidney, and/or 

other sample types—in sufficient amounts are needed 

for analysis (69), but this requirement frequently cannot 

be achieved in those accidents in which bodies are scattered, disintegrated, commingled, contaminated, and/or 

putrefied. Glucose concentrations in vitreous fluid and 

urine samples are determined, and in those situations 

wherein glucose levels are elevated, blood hemoglobin 

A1c (HbA1c; glycosylated hemoglobin) is also measured 

to monitor diabetic pilots, ensuring that the disease was 

in control at the time of accident, and to discover other 

pilots with undiagnosed or unreported diabetes (55). The 

postmortem forensic samples are submitted to CAMI in 

TOX-BOX evidence containers. The contents of a TOXBOX kit and types, amounts, and analytical suitability 

of postmortem specimens are detailed in a previously 

published article (69). 

4.2 Analytical Components

Evidence containers with samples should be received 

in a secured, specific area of the toxicology facility, and 

the samples should be accessioned following the standard 

operating procedure of the laboratory. Depending upon 

the types and amounts of submitted samples and the mission of the laboratory, the following analytical toxicology 

tests should be performed (69):

1) Blood CO as COHb by a spectrophotometric 

method and confirmation by gas chromatography

2) Blood CN ̄ by a colorimetric method and confirmation by another method, such by high-performance 

liquid chromatography 

3) Ethanol/volatiles in vitreous fluid, urine, blood, 

brain, muscle, and/or other tissues by dual capillary 

column-flame ionization detection by headspace gas 

chromatography

Note: The presence of ethanol in liquid samples—vitreous fluid, urine, and blood—should be 

confirmed by a second method such as radiative 

energy attenuation. In those cases wherein ethanol is positive in urine, urinary concentrations of 

serotonin metabolites—5-hydroxytryptophol 

(5-HTOL) and 5-hydroxyindole-3-acetic acid (5-

HIAA)—should be measured by liquid chromatography-mass spectrometry and their ratio should be 

calculated to conclude whether ethanol found in 

the samples is from sources other than ingestion. A 

concentration ratio value of < 15 pmol/nmol is not 

consistent with ethanol ingestion; a value ≥ 15 pmol/

nmol is suggestive of ethanol ingestion (153, 154).
19

4) Blood and other tissue samples should be screened 

for: 

a) Controlled substances—amphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, 

methamphetamine, opiates, and phencyclidine—by radioimmunoassay 

b) Prescription and nonprescription drugs by highperformance liquid chromatography and gas 

chromatography-mass spectrometry

c) Additional drugs in blood—acetaminophen, 

phenytoin, quinidine, salicylate, and theophylline—by fluorescence polarization immunoassay.

5) Urine should be screened for:

a) Controlled substances—amphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, 

methamphetamine, opiates, and phencyclidine—

by fluorescence polarization immunoassay

b) Prescription and nonprescription drugs by highperformance liquid chromatography and gas 

chromatography-mass spectrometry

c) Additional drugs—acetaminophen, phenytoin, propoxyphene, quinidine, salicylate, and 

theophylline—by fluorescence polarization 

immunoassay.

6) Confirmatory/quantitative analysis should be performed in the samples wherein drug(s) was found 

during initial analyses (screening). In other words, 

confirmatory/quantitative analyses should be performed in the aliquots of the sample type, which 

was determined as presumptively positive for drug(s) 

during the initial analysis (screening), and of at least 

1 additional sample type (if available) of the case. 

Preferred sample types are blood and urine, but other 

sample types could also be used. Depending upon 

the type of analyte, gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry, 

or any other specific techniques could also be used 

for confirmatory/quantitative analyses.

7) Glucose in vitreous fluid and urine could be measured 

enzymatically and HbA1c in blood by latex immunoagglutination inhibition methodology. Presence of 

glucose in vitreous and urine could be reconfirmed 

by color-sensitive reagent strips. 

8) Sometimes, DNA profiling should also be performed 

on the samples of a case to ensure that the submitted samples originated from the same source. This 

approach becomes necessary when there is a reason 

to believe that the samples might have been commingled or mismatched with the samples of other 

victims during the sample collection (70).

9) Throughout the entire process of toxicological 

evaluation—that is, from receiving the samples to 

dispatching the analytical reports—a high level of 

quality assurance/quality control should be maintained (4, 260); this aspect could be easily exemplified by the previously described FAA’s Postmortem 

Forensic Toxicology Proficiency-Testing Program (4, 

54, 260). 

10) The chain-of-custody of postmortem forensic 

samples and all records, including analytical data, 

should be securely maintained throughout the entire 

forensic evaluation process. 

Since the presence of drugs in a pilot’s system also 

suggests possible associated medical conditions for 

which they might have been taken, identification and 

quantification of parent drugs and their metabolites in 

multi-specimens are of relevance in the field of forensic 

science (56). Demonstrating the presence of drug metabolites such as ∆9

-tetrahydrocannabinol (THC) carboxylic 

acid of THC and benzoylecgonine of cocaine provides 

compelling evidence for use/abuse to the parent drug and 

facilitates interpretation of results and investigation of a 

case, particularly when the metabolites are pharmacologically active. Such analyses might not be as helpful if the 

metabolites are also marketed or available as drugs.

4.3 COHb and Blood CN ̄ Concentrations

Although in-flight fires in modern aircraft are rare, 

post-crash fires do occur (53, 64, 68, 177). Fire-involved 

civil passenger aircraft accidents claiming considerable 

number of fatalities have been documented (32, 126). 

In aviation accidents, COHb and blood CN ̄ analyses 

are performed to establish possible exposure of victims 

to smoke from in-flight/post-crash fires or to CO from 

faulty exhaust/heating systems. The elevated COHb, as 

well as CN ̄, in blood would suggest that the victim was 

alive and inhaled smoke. If only COHb is elevated, the 

accident (or death) could be attributed to the contamination of the aircraft interior by CO. 

The toxicological assessment of 485 fatal aircraft accidents that occurred in the United Kingdom between 

1955 and 1979 found COHb concentrations ≥ 10% in 

90 fatalities of the 439 evaluated (143). In another study 

for the 1967–1972 period, toxicology revealed elevated 

COHb of direct importance in 19% of the 113 accidents 

(23). Blood analysis of pilot fatalities of general aviation 

accidents (October 1968–September 1974) revealed 

COHb in excess of 10% in 79 of the 1,345 cases and 

elevated CN ̄ in 16 of the 1,345 cases (165). Elevated 

COHb was reported in 13 of the 2,449 pilots killed in 

general aviation operations (1973–1977) and was due to 

faulty heaters or exhaust systems (166). Three cases with 
20

COHb > 10% have been reported in 202 general aviation accidents in a 1970 study (255). In an FAA study, 

analysis of samples from 377 aviation fatalities during 

October 1988–September 1989 concluded COHb at < 

10% in 94% of the cases and cyanide at < 0.5 μg·ml−1 in 

96% of the cases (161). Toxicological findings in military 

aircraft fatalities investigated by the Division of Forensic 

Toxicology at the U.S. Armed Forces Institute of Pathology from 1986 to 1990 suggested COHb concentrations 

> 10% in 4.3% of the 535 cases (159). 

According to a 2001 study by Chaturvedi et al. (68), 

1,571 (41%) fatalities (1,012 aviation accidents) out of 

the 3,857 fatalities (2,837 aviation accidents) occurring 

during 1991–1998 were fire-associated. There were 1,820 

non fire-related accidents, and the fire status of 5 accidents 

was unknown. There were fewer fire-related fatalities and 

associated accidents in the category wherein COHb ≥ 

10% and CN ̄ ≥ 0.25 μg·ml−1 than that in the category 

of wherein COHb < 10% and CN ̄ < 0.25 μg·ml−1. No 

in-flight fire was documented in the former category; 

however, in-flight fires were reported in 14 accidents (18 

fatalities) in the latter category. There were 15 non-fire 

accidents involving 17 fatalities. In these fatalities, only 

COHb (10–69%) was elevated. This study suggested that 

aviation fire accidents were fewer than non-fire accidents 

and confirms that aviation accidents related to in-flight 

fires and CO-contaminated interiors are rare occurrences. 

(Readers may also refer to the Aviation Combustion Toxicology section for additional details.)

4.4 Ethanol

Depending upon the nature of a fatal aviation accident, 

the bodies of victims are frequently scattered, disintegrated, and/or putrefied. It is well-established that the 

body is invaded by microbes after death, and these living 

micro-organisms are involved in putrefaction processes, 

leading to the postmortem production of ethanol in the 

body (22, 75, 160, 163). The extent of putrefaction is 

linked to the condition of the body, which is affected by 

the severity of injuries, the time between the death and 

the discovery of the body (postmortem interval), and the 

environmental factors. Indeed, the postmortem production of ethanol in aviation accidents has been an issue 

investigated for many years (89), but the production of 

ethanol after the postmortem collection of fluid samples 

can be minimized by collecting them in containers containing sodium fluoride and storing the collected samples 

in cold (69, 89, 172). Ethanol production by Candida 

albicans in postmortem human blood samples has been 

reported, and the necessity of immediately adding sodium 

fluoride to samples for ethanol analysis to prevent further 

ethanol production, if any, has been reemphasized (301). 

A polymerase chain reaction (PCR)-based method for 

detecting the presence of common ethanol producing 

microbial contaminants—Escherichia coli, Proteus vulgaris, and Candida albicans—in human blood has been 

published by using a set of DNA primers designed for 

use in PCR to amplify and detect the genomic DNA 

from humans and the 3 test microorganisms (163). This 

method is suitable for rapidly identifying microbial contaminants in postmortem blood, as well as solid tissue, 

samples (163, 287).

Because of the impact generally encountered during 

aircraft crashes, extensive abdominal damage and open 

wounds frequently occur in the fatalities. Such damage 

and wounds, thus, increase the potential for microbial 

invasion and for putrefaction; interpretation of ethanol 

concentrations in autopsied specimens from victims is 

highly arguable, and great caution is needed to reach 

valid conclusions of whether the deceased had consumed 

ethanol before death (160). In the past, the postmortem 

ethanol production was inferred from the presence of 

acetaldehyde, acetone, 2-butanol, and other volatiles, 

but this basis may not have always been correct (42). For 

example, in a study involving aviation accident fatalities, 

several cases with postmortem ethanol had no other volatiles, and volatile compounds were found in several cases 

where no ethanol was present (42). In addition, a case 

was found in which the relative ethanol concentrations 

in blood, bile, and vitreous humor were consistent with 

the ingestion of ethanol, but acetaldehyde, acetone, and 

2-butanol were also found in blood. These observations 

indicate that the presence or absence of other volatiles does 

not necessarily establish postmortem ethanol production 

(42).Determination of ethanol concentrations in various 

sample types—vitreous humor, urine, brain, liver, kidney, 

and muscle—is helpful in establishing the distribution of 

ethanol. Based upon the distribution findings, it could 

be scientifically deduced whether ethanol was consumed 

before death or produced postmortem. The presence 

of ethanol in blood and its absence in vitreous fluid or 

brain would be indicative of postmortem formation of 

ethanol. Interpretation of postmortem production of 

ethanol and other associated factors has been covered in 

a critical review by O’Neal and Poklis (205). 

Of the 485 U.K. fatal aircraft accidents (1955–1979), 

28 were found to have medical cause (143). Seven of 

these 28 crashes were due to alcohol consumption. Dur-

ing 1967–1972 in the UK, aircraft accident toxicology 

revealed that the presence of ethanol was of importance 

in 7% of the 113 accidents (23). In the U.S., blood 

ethanol concentrations were found in excess of 0.05% in 

117 of the 1,345 general aviation accident pilot fatalities 

(October 1968–September 1974) (165), in 226 of the 

2,623 pilots killed during agricultural and general aviation operations (1973–1977) (166), and in 28 of the 202 
21

pilots involved in fatal general aviation accidents (255). 

In an FAA study, the presence of ethanol at > 10 mg·dl−1

was found in 14.8% of the 377 aviation fatalities during 

October 1988 to September 1989, but only 4.5% were 

determined to be due to ethanol ingestion (161). Positive ethanol findings in military aircraft fatalities from 

1986–1990 were suggestive of postmortem formation 

than antemortem consumption (159). 

In a study by Canfield et al. (42), 79 (8%) of 975 

victims of fatal aircraft accidents (1989–1990) had blood 

ethanol ≥ 0.04% (40 mg·dl−1), a legal blood alcohol concentration under the FAA regulation at which no person 

may operate or attempt to operate an aircraft (48, 233). 

Based on the distribution of ethanol in urine, vitreous 

humor, blood, and tissue (42), it was determined that 

21 of the positive cases (27%) were from postmortem 

ethanol production. Postmortem ethanol production 

was > 0.15% (150 mg·dl−1) in 2 cases. Additionally, 22 

(28%) of the positive cases were found to be from the 

ingestion of ethanol. The origin of the ethanol could not 

be established in 36 cases (45%). A study involving the 

postmortem toxicology analysis (1989–1993) of 1,845 

aviation accident pilot fatalities revealed the presence 

of ethanol at or above the legal limit of 0.04% in 146 

pilots (35, 48, 233). Similarly, ethanol at or above the 

legal limit was found in 124 out of 1,683 pilots during 

1994–1998 (41) and in 101 out of 1,587 pilots during 

1999–2003 (58, 59). The presence of ethanol with selective serotonin reuptake inhibitors (SSRIs) (6) and with 

first-generation H1

 antihistamines (250) has also been 

reported in aviation accident pilot fatalities. 

The research on the production of ethanol has now 

been focused on developing various biochemical tests or 

markers of postmortem synthesis of ethanol (160). These 

tests/markers include the urinary metabolites of serotonin 

and non-oxidative metabolites of ethanol such as ethyl 

glucuronide (34, 133, 153, 154, 160, 195). Additionally, 

ethyl sulfate and the ratio between 5-hydroxytryptopholglucuronide and 5-HIAA have further been emphasized 

as biomarkers for recent alcohol ingestion with longer 

detection times than measurement of ethanol itself (148).

However, there has been debate about the total reliability 

of the biomarkers (140). The formation of ethyl glucuronide and ethyl sulfate has been reported even following 

inhalation of ethanol vapors (155). Disappearance of 

ethyl glucuronide during heavy putrefaction has also been 

implied (149). On the other hand, ratios of concentrations of serotonin metabolites, 5-HTOL and 5-HIAA, in 

urine have effectively been used for concluding whether 

ethanol found in the samples is from sources other than 

ingestion (34, 133, 153, 154). The use of the urinary 

5-HTOL:5-HIAA concentration ratio as a marker of 

recent ethanol consumption stems from the fact that the 

oxidative deamination of serotonin to 5-HIAA is altered 

after ethanol consumption (89). Such alteration causes 

an increase in the concentration of 5-HTOL, which 

is normally < 1% of 5-HIAA. Recent consumption of 

ethanol increases this proportion of serotonin metabolites. 

Accordingly, a concentration ratio (5-HTOL:5-HIAA) 

value of < 15 pmol/nmol is not consistent with ethanol 

ingestion, while a value ≥ 15 pmol/nmol is suggestive of 

ethanol ingestion (34, 153, 154). 

4.5 Drugs

4.5.1 Commonly Used and Abused Drugs

Although the topic of taking medications by aviators has 

been touched upon by Hill (143) in the 1986 study covering 485 U.K. fatal aircraft accidents (1955–1979), the 

U.K. aircraft accident toxicology experience (1967–1972) 

is elaborated in a study by Blackmore (23). This study 

involved 113 aircraft, encompassing 184 crew and 207 

passengers. Cyclopenetamine, methaqualone, salicylate, 

and valium were detected in 4 pilots of the fatal accidents. In the U.S., a toxicological study with 202 pilot 

fatalities disclosed the presence of drugs—amitriptyline, 

barbiturate, chloroquine, chlorpromazine, morphine, 

perphenazine, pheniramine, and quinidine—in 7 pilots 

(255). A summary of toxicological findings of fatal general aviation accidents (October 1968–September 1974) 

suggested the presence of drugs in 16 of 1,345 fatalities 

(165). In another study (166), the use of drugs has been 

reported to be less in agricultural pilots (1.1% of 174) 

than in general aviation pilots (4.9% of 2,449) during 

the period of 1973–1977. Toxicological evaluations of 

samples from 377 aviation fatalities during October 1988 

to September 1989 concluded that 12.6% of the cases 

were positive for 1 or more drugs (161). Cannabinoids 

were found in 1.3% of the cases and benzoylecgonine 

in 1.6%. Acetaminophen and salicylate were the most 

frequently encountered drugs. Including chloroquine and 

nicotine, over-the-counter analgesics, antihistaminics, 

and sympathomimetics have been identified in military 

aircraft fatality cases from 1986 to 1990 (159). 

Between 1989 and 1993, postmortem samples from 

1,845 pilots were toxicologically analyzed at CAMI (35). 

Controlled dangerous substances of Schedules I and II 

(amphetamine/methamphetamine, barbiturates, cocaine, 

codeine/morphine, marihuana, methaqualone, phencyclidine, and synthetic opiates) were found in 74 pilots and 

of Schedules III–V (benzodiazepines, phendimetrazine, 

and phentermine) in 28 [for the classification of Scheduled substances, see ref. (47)]. Prescription drugs were 

found in 110 pilots, over-the-counter drugs in 207, and 

ethanol in 146. Analyses of postmortem samples from 

1,683 pilots during 1994 to 1998 disclosed the presence of controlled dangerous substances of Schedules I 
22

and II (amphetamine/methamphetamine, barbiturates, 

cocaine, codeine/morphine, marihuana, methaqualone, 

phencyclidine, and synthetic opiates) in 89 pilots and of 

Schedules III–V (benzodiazepines, fenfluramine, pentazocine, phendimetrazine, phentermine, propoxyphene/norpropoxyphene) in 49 pilots (40, 41). Prescription drugs 

were detected in 240 pilots, over-the-counter medications 

in 301, and ethanol in 124. In continuation of these 2 

preceding studies (35, 40, 41), an epidemiological assessment was made for an additional period of 5 years 

(1999–2003) (58, 59). Of 1,629 fatal aviation accidents 

from which CAMI received biosamples, there were 1,587 

accidents wherein pilots were fatally injured. Drugs 

and/or ethanol were found in 830 of the 1,587 fatalities. 

Controlled substances of Schedules I and II (amphetamine/methamphetamine, barbiturates, cocaine and its 

metabolite(s), codeine/morphine, marihuana, 3,4-methylenedixoymethamphetamine, and synthetic opiates) 

and of Schedules III–V (benzodiazepines, phentermine, 

propoxyphene/norpropoxyphene, and zolpidem) were 

detected in 113 and 42 pilots, respectively. Prescription 

drugs were present in 315 pilots, nonprescription drugs 

in 259, and ethanol in 101. More than 1 drug was present 

in some fatalities, thus those fatalities were counted more 

than once—that is, for each drug or ethanol. Barbiturates 

included butalbital, pentobarbital, and/or phenobarbital; 

marihuana meant THC and/or THC carboxylic acid; 

synthetic opiates include hydrocodone, hydromorphone, 

meperidine, oxycodone, and/or their metabolites; and 

benzodiazepines entailed α-hydroxyalprazolam, alprazolam, diazepam, midazolam, nordiazepam, oxazepam, 

and/or temazepam. Prescription drugs found in the 3 

studies (1989–1993, 1994–1998, and 1999–2003) are 

tabulated in Table VII (35, 40, 41, 58, 59). Commonly 

found non-prescription drugs were acetaminophen, 

chlorpheniramine, dextromethorphan, doxylamine, 

ephedrine, meclizine, (–)-methamphetamine, oxymetazoline, phenylpropanolamine, pseudoephedrine, quinine, 

salicylate, and triprolidine. These drugs were primarily 

associated with drug preparations and formulations used 

to alleviate allergy and cold symptoms. 

Any increase seen in the prevalence of drugs during 

the 15-year period (1989–1993, 1994–1998, and 1999–

2003) (35, 40, 41, 58, 59) could perhaps be attributed 

to the possibilities of scientific and technical advances in 

the sensitivity of analytical methods, genuine authorized 

medical use of such drugs, and/or their real abuse. Narcotic 

analgesics found in pilot fatalities could have been administered by emergency health care providers at accident 

scenes or at hospitals for pain reduction and/or surgical 

procedures. The presence of abused drugs—such as, 

amphetamine/methamphetamine, cocaine, marihuana, 

and 3,4-methylenedixoymethamphetamine—could have 

been associated with their unauthorized use. Atropine and 

lidocaine might have been administered by health care 

providers for resuscitation. The presence of prescription 

drugs found in the fatalities reflected the current trends 

in the popularly dispensed groups of medications—antihypertensives and antidepressants—in the U.S. (58, 59). 

Many of the prescription and nonprescription drugs, 

including the controlled substances, present in the pilot 

fatalities have the potential for impairing performance, 

thereby adversely affecting the ability of an individual 

to optimally pilot an aircraft. Findings from these stud-

ies support the FAA's programs, including the FAA's 

drug-testing program, aimed at identifying potentially 

incapacitating medical conditions and reducing the usage 

of performance-impairing drugs or ethanol (49, 102). 

4.5.2 SSRIs

The prevalence of SSRIs was evaluated in pilot fatalities 

of civil aviation accidents that occurred during 1990–2001 

(5, 6). Of 4,184 fatal civil aviation accidents, there were 

61 accidents in which pilot fatalities had SSRIs. Blood 

concentrations of SSRIs were 11–1,121 ng·ml−1 for fluoxetine; 47–13,102 ng·ml−1 for sertraline; 68–1,441 ng·ml−1

for paroxetine; and 314–462 ng·ml−1 for citalopram. In 39 

pilots, other drugs—such as, analgesics, antihistaminics, 

benzodiazepines, narcotic analgesics, and/or sympathomimetics—and/or ethanol were also present. Although 

blood SSRI concentrations ranged from subtherapeutic 

to toxic levels, the interactive effects of other drug(s) and 

ethanol in producing adverse effects in the pilots cannot 

be ruled out. To establish whether these pilots had disqualifying psychological conditions, including depression, 

and had properly reported the use of the antidepressants, 

the aeromedical history of these pilots was examined and 

reported by Sen et al. (248, 249). 

Based upon the distribution of fluoxetine in 10 fatal 

aviation accident cases, its distribution coefficients, expressed as specimen type/blood ratios, were determined 

to be 0.9 ± 0.4 for urine, 0.10 ± 0.03 for vitreous humor, 

9 ± 1 for bile, 38 ± 10 for liver, 60 ± 17 for lung, 9 ± 3 

for kidney, 20 ± 5 for spleen, 2.2 ± 0.3 for muscle, 15 

± 3 for brain, and 10 ± 2 for heart (151, 175). Blood 

concentrations of this SSRI in these fatalities ranged from 

21 to 1,480 ng·ml−1. 

4.5.3 First-Generation H1 Antihistaminics

Although first-generation H1

-receptor antagonists 

cause drowsiness and sedation leading to potential performance impairment, these antihistamines are popularly 

used for alleviating allergy and cold symptoms. The 

prevalence of these antagonists was evaluated in pilot 

fatalities of civil aircraft accidents that occurred during a 

16-year (1990–2005) period (250, 251). Of 5,383 fatal 
23

Table VII. Prescription Drugs Found in Pilot Fatalities 

Drugs and Their Metabolites 

Aminophenazone Labetalol 

Amitriptyline/Nortriptyline Lidocaine 

Amlodipine Maprotiline 

Atenolol Metoclopramide 

Atropine Metoprolol 

Azacyclonol Minoxidil 

Benzocaine Mirtazapine 

Bisoprolol Moricizine 

Brompheniramine Nadolol 

Bupropion/Metabolite Naproxen 

Carbamazepine Nizatidine 

Cetirizine Orphenadrine 

Chloroquine Pantoprazole 

Cimetidine Paroxetine 

Citalopram/Metabolite(s) Phenyltoloxamine 

Cyclizine Phenytoin 

Cyclobenzaprine Procainamide/N-Acetylprocainamide 

Diltiazem Promethazine 

Diphenhydramine Propoxyphene/Norpropoxyphene 

Doxazosin Propranolol 

Doxepin/Nordoxepin Quinidine 

Etomidate Ranitidine 

Fenoprofen Sertraline/Desmethylsertraline 

Fluconazole Sildenafil/Metabolite(s) 

Fluoxetine/Norfluoxetine Theophylline 

Gemfibrozil Thiopental 

Griseofulvin Tramadol 

Hydrochlorothiazide Trazodone 

Hydroxyzine Triamterene 

Ibuprofen Trimethoprim 

Imipramine/Desipramine Venlafaxine/Desmethylvenlafaxine 

Ketamine Verapamil/Norverapamil 
24

aviation accidents, there were 338 accidents wherein pilot 

fatalities (cases) were found to contain brompheniramine, 

chlorpheniramine, diphenhydramine, doxylamine, pheniramine, phenyltoloxamine, promethazine, and triprolidine. Antihistamines were detected alone in 103 fatalities, 

while other drug(s) and/or ethanol were also present in an 

additional 235 fatalities. More than 1 antihistamine was 

detected in 35 fatalities. Although blood was not available 

for analyses in all cases, blood concentrations (ng·ml−1) 

were: 5–200 (n = 8) for brompheniramine; 4–6,114 (n 

= 67) for chlorpheniramine; 9–3,800 (n = 125) for diphenhydramine; 10–1,309 (n = 33) for doxylamine; and 

4 (n = 1) for phenyltoloxamine. These levels were in the 

sub-therapeutic to toxic range. In an earlier study (262), 

47 (2.2%) accidents that occurred during 1991–1996 

were associated with chlorpheniramine. Related to these 

accidents, 16 pilots had only chlorpheniramine at 109 

ng·ml−1 (n = 4) in blood and 1,412 ng·g−1 (n = 12) in 

liver. Other drugs were also present in the remaining 

cases, wherein chlorpheniramine concentrations were 

93 ng·ml−1 (n = 18) in blood and 747 ng·g−1 (n = 12) in 

liver. Ninety-five percent of all quantitated blood values 

were at or above the therapeutic level (10 ng·ml−1). 

4.5.4 Other Drugs

4.5.4.1 Selegiline

Stereochemical determination of selegiline metabolites 

in postmortem biological specimens from an aviation 

accident pilot fatality was accomplished to deduce that 

the pilot was being treated for Parkinson’s disease (164). 

Such analytical differentiation between dextrorotatory and 

levorotatory methamphetamine/amphetamine has been 

applied to establish the optical purity of methamphetamine found in toxic concentration in a fatally injured 

pilot of an aviation accident (57). 

4.5.4.2 Sildenafil

Concentrations of sildenafil and its active metabolite 

have been reported in various biological samples from 

victims from 6 separate aviation fatalities (150, 173).

4.5.4.3 Vardenafil

The postmortem distribution of vardenafil, with an 

unusually high blood concentration, has been evaluated 

in an aviation accident victim (152).

4.5.4.4 Butalbital

In an attempt to estimate blood butalbital concentrations from the drug levels in available tissues, distribution of butalbital was studied in various postmortem 

tissues and fluids from aviation accident fatalities (176). 

The distribution coefficients for butalbital, expressed as 

specimen type/blood ratios, were (n = 2–4): 0.66 ± 0.09 

for muscle, 0.98 ± 0.09 for kidney, 0.87 ± 0.06 for lung, 

0.75 ± 0.03 for spleen, 0.96 ± 0.07 for brain, 2.22 ± 0.04 

for liver, and 0.91 ± 0.17 for heart. 

4.6 Elevated Glucose and HbA1c

Vitreous fluid and urine samples from pilots fatally 

injured in aviation accidents are analyzed for glucose 

and blood for hemoglobin A1c (HbA1c) (19, 36, 37, 

291). In an epidemiological study involving 1,335 pilots 

(1998–2005), 43 were found to have elevated glucose in 

vitreous fluid ( > 125 mg·dl−1) and/or in urine (> 100 

mg·dl−1). Of the 20 pilots whose blood samples were 

analyzed, 9 had > 6% HbA1c (55). Four of the 9 pilots 

were known diabetics, while 5 were unknown diabetics. 

A considerable number of pilots (30 of 43) had elevated 

glucose and HbA1c (5 of 20), suggesting undiagnosed/

unreported diabetic conditions. 

5 CABIN AIR CONTAMINATION

5.1 Introductory Aspects

Quality of air in cabins of aircraft has been a topic of 

debate and discussion since at least the 1970s. Aerospace 

air pollution issues—that is, cabin air quality of aircraft 

and space vehicles—have been succinctly addressed in 

an article by Patterson and Rayman (210). These issues 

are in view of the facts that the crews must work, sleep, 

and live in the cabin environments of aircraft and space 

vehicles. Throughout the world, the possible adverse effects of cabin atmosphere contents on the health of air 

crews and travelers have been evaluated (30, 31, 122, 

134, 217, 218, 220, 285, 300). Aircraft cabin air qualityrelated bills in the U.S. Congress and reports of the U.S. 

National Academy of Sciences have been in the limelight 

in the field of aerospace medicine (217, 218, 221). More 

than 30 years ago, the quality of cabin air was apparently 

not an issue in commercial aviation, and the incidence 

of disease through airborne vectors or toxic fumes was 

uncommon (3). However, modern jet airliners may have 

the threat of disease because their ventilator systems are 

designed for optimum efficiency, leaving them exposed 

to lapses in the recycling of clean air and blocking fumes 

from jet engine exhausts from entering the aircraft cabin 

areas. Aero-toxic fumes are most common in the cockpit, 

and the crew members are the most susceptible to the 

aero-toxic syndrome (3). In a comprehensive review of 21 

studies examining the effect of the airliner cabin environment and other factors on the health and comfort of flight 

attendants, Nagda and Koontz (197) found that various 

complaints and symptoms reported by the attendants 

appeared to be associated with their job duties and with 

the cabin environment. The “dryness” symptoms were 

attributable to low humidity and “fatigue” symptoms with 
25

factors such as disruption of circadian rhythm. Certain 

flight attendants complaints were consistent with possible 

exposure to air pollutants, but that relationship has not 

been established with a view that such complaints also 

were consistent with causes other than poor air quality. 

In spite of health issues associated with air travel, there 

are enormous benefits to travelers, to commerce, to international affairs, and to health (96). 

Stresses, like airport tumult, barometric pressure 

changes, immobility, jet lag (238), noise, vibration, and 

radiation, imposed by commercial flights upon travelers 

and in-flight illness and medical care capability aboard 

U.S. air carriers have been addressed in a review article 

(219). Since the “cabin air quality” topic has been of 

concern and controversy, the Aerospace Medical Association (AsMA) has reviewed the scientifically accepted 

facts in the different elements (such as pressurization, 

ventilation, contamination, humidity, and temperature) 

associated with aircraft cabin atmospheres (270). AsMA 

recommended that regulators, airlines, and scientific associations work together on the issue of cabin air quality 

because no amount of technical data alone would solve 

the problem. Aircraft cabin CO2

 concentrations calculated 

from the published ventilation ratings were found to be 

intermediate to these sets of results obtained by actual 

measurement. These findings are used to arrive at recommendations for aircraft builders and operators to help 

improve aircraft cabin air quality at minimum cost (145). 

Based on the passenger aircraft cabin air quality covering 

trends, effects, societal costs, and proposals, suggestions 

for air quality improvement were made resulting in a 

net, multi-stakeholder savings and improved passenger 

comfort (146). Aviation industry and passenger perspectives in relation to cabin air quality have been evaluated 

by Hocking (147). Accordingly, recommendations and 

suggestions were made for aircraft builders, operators, 

and passengers. Those recommendations/suggestions 

would help improve aircraft cabin air quality and the 

partial pressure of oxygen that is available to passengers at 

minimal cost and enhance their comfort and decrease their 

risk of illness. In an overview by Rayman (221), recommendations have been made on how the cabin air quality 

issue may be resolved. Furthermore, a literature review 

demonstrated that airliner cabin air quality is adequate 

and does not compromise aircrew health (271), though 

the need for further studies was acknowledged.

5.2 Aircraft Cabin Air 

Fatigue in aircrew members performing frequent and 

long-range flights has been linked to aircraft-related noise, 

temperature, cabin pressure, ventilation, atmosphere 

quality, humidity, jet lag, and flight characteristics (122, 

285). Ventilation adequacy, cigarette fires, and pilot 

health issues have been addressed (122). Presence of less 

fresh air in cabin was acknowledged, but there was more 

than enough oxygen for human consumption (134). 

The concentration of microorganisms in airline cabin air 

was found to be much lower than their concentration in 

ordinary city locations (292), concluding that the small 

number of microorganisms found in the U.S. airliner 

cabin environments does not contribute to the risk of 

disease transmission among passengers. In a 1997 study 

of Airbus aircraft (95), the number of particles in cabin 

air was compared with fresh air and re-circulated air. 

Also, microbiological contamination and volatile organic 

compound concentrations in cabins were investigated. 

The particles were found to be mainly emitted by passengers, especially smokers, and the recirculation air 

contained a lower or equal amount of particles compared 

to the fresh air, whereas the amount of bacteria exceeded 

reported concentrations within other indoor spaces. The 

detected microbes were mainly non-pathogenic, and 

the concentrations of volatile organic compounds were 

well below threshold values. Modern high efficiency 

particulate air (HEPA)-filters minimize an accumulation 

of bacteria and viruses within the recirculation flow of 

the cabin air, thereby significantly reducing the overall 

risk of getting infectious diseases, compared with other 

means of transportation (20). The issue of the flying 

fitness of patients with infections has been discussed 

(132). Cargo, as well as passenger, aircrafts have proven 

to be vectors of disease because they transport humans, 

mosquitoes, other insects, and animals (96). The occurrence of transmission of tuberculosis and influenza 

to other travelers has been reported, and vectors for 

yellow fever, malaria, and dengue have been identified 

on aircraft. However, studies of ventilation systems and 

patient outcomes suggest that the spread of pathogens 

occurs rarely during flights (169).

A review of reported air concentrations of organic 

compounds in cabins indicated that contaminant levels in 

aircraft cabins are similar to those in residential and office 

buildings (198). However, there were 2 exceptions. First, 

levels of ethanol and acetone—indicators of bio-effluents 

and chemicals from consumer products—were higher in 

aircraft than in home or office environments and in other 

transportation modes; second, levels of certain chlorinated 

hydrocarbons and fuel-related contaminants were higher 

in residential/office buildings than in aircraft. The levels 

of chemicals such as m- and/or p-xylenes tend to be lower 

in aircraft. Although cabin air is filtered prior to recirculation to remove volatile organic compounds and odor by 

using adsorbers, such devices may not be installed in all 

aircraft and may not be capable of removing all pollutants. Therefore, the photo-catalytic air filtering approach 

was developed, and it seems promising to resolve odor 
26

problems in aircraft (127). The overall efficiency of the 

photo-catalytic unit is the function of the characteristics of 

compounds (toluene, ethanol, and acetone) that challenge 

the unit. Toluene was apparently found to be the most 

difficult compound to be oxidized. The photo-catalytic 

technique used by the tested prototype unit is able to 

partially oxidize volatile organic compounds, but one 

has to be aware that some toxic intermediate chemical 

reaction products such as formaldehyde and acetaldehyde 

are also produced during the oxidation process.

High concentrations of ozone can lead to upper 

respiratory problems and of CO2

 may cause hyperventilation (20). Additionally, the mucous membranes of 

the respiratory tract are dried out due to the extremely 

low humidity of the cabin air. In a 2000 study by Backman and Haghighat (9), high CO2

 concentrations and 

low humidity levels were found in the Airbus 320. The 

highest humidity level was determined in the DC-9; the 

lowest CO2 concentration in the Boeing 767. The authors 

concluded that poor air quality may cause intolerance 

to contact lenses, dry eyes, and may be a health hazard 

to both passengers and crew members. In the U.S. Air 

Force C-5 cabin air, CO and CO2

 concentrations were 

found to be well below health effect threshold, relative 

humidity a lowest level of 3%, and ozone at relatively 

low concentrations (141). The influence of ozone on 

self-evaluation of symptoms in a simulated aircraft cabin 

indicated that the air quality and 12 of the symptoms, 

including eye and nasal irritation, lip and skin dryness, 

headache, dizziness, mental tension, and claustrophobia, 

were established to be significantly worse (p < 0.05) for 

the “ozone” condition, compared to the “no ozone” 

condition (265).

During intercontinental flights (180), CO2

 levels were 

below 1,000 ppm in 97% of the cases and humidity was 

very low (5%). Low humidity might conceivably be a 

factor for mucosal irritation experienced by travelers and 

flight attendants in aircraft cabins (178, 196, 280), and 

tobacco-smoking onboard might contribute to significant pollution from respirable dust (178, 180, 294). An 

investigation on the influence of air humidification on 

intercontinental flights on the perception of cabin air qual-

ity among airline crew concluded that relative humidity 

can be slightly increased by using a ceramic evaporation 

humidifier, without any measurable increase of microorganisms (181). The evaluation of the optimum balance 

between fresh air supply and humidity from 7-h exposures 

in a simulated aircraft cabin exhibited that increasing 

the relative humidity in the cabin to 28% by reducing 

outside flow to 1.4 l·s

−1 per person did not reduce the 

intensity of the symptoms that are typical of the aircraft 

cabin environment. However, this adjustment intensified 

complaints of headache, dizziness, and claustrophobia, 

due to the increased level of contaminants (266). 

The assessment of the contribution of secondhand 

smoke to aircraft cabin air pollution and flight attendants 

has been made relative to the general population and was 

determined that ventilation systems massively failed to 

control secondhand smoke air pollution in cabins (224). 

However, smoking is now prohibited by most airlines and 

air pollution caused by smoking is no longer a relevant 

issue. Additional studies further emphasize that the relative 

air humidity was very low on intercontinental flights, and 

particle levels were high on flights with passive smoking 

(179). These findings suggested the need for improving 

cabin air quality by better control of cabin temperature, 

air humidification, air filtration (HEPA filters), and sufficient air exchange rate on all aircraft types.

5.3 Space Vehicle Cabin Air

Astronauts work, sleep, and live in space vehicles (210), 

and there is a strong potential for the slow and insidious 

buildup of toxic substances—such as refrigerants, CO, 

HCN, CO2, ammonia, and other organic compounds—in 

the space vehicle cabin atmosphere. Toxic substances could 

also be released rapidly in high concentrations. The sources 

of these substances could be from off-gassing, human 

metabolism, payload chemicals, and thermal degradation 

of materials. Therefore, the protection of the astronauts’ 

health and the prevention in their performance decrements are crucial. A major concern in the space cabin is 

the establishment of maximum allowable concentrations 

of potentially toxic substances. Such establishment should 

be based upon the facts that astronauts live in a closed 

environment of space vehicles 24 h a day, for weeks or 

even months, in comparison to an 8-h working shift on 

the Earth. Contracting microbes in the space cabin is of 

concern since crew members would release many bacteria 

into the environment, and their droplets in microgravity 

remain suspended in the atmosphere, thus making their 

exposures more likely. How microgravity affects the immune system of humans has not been well-established. 

Therefore, the monitoring of microorganisms and toxic 

substances is crucial in the space vehicle cabin atmosphere. 

Methods and means of qualitative and quantitative air 

monitoring on the International Space Station are sufficient for air control in emergency situations such as local 

fire and toxic leak. Also, the Station’s air quality has suited 

to the adopted standards and crew safety requirements. 

However, there is a need to improve the space cabin air 

monitoring (208).

In the area of monitoring, the development of mass 

spectrometry instrumentation to support the goals of the 

U.S. space program (209) has taken place for studying the 
27

composition of planetary atmospheres and monitoring air 

quality on manned space missions. The mass spectrometry 

instruments deployed on the Pioneer Venus and the Mars 

Viking Lander missions have been reviewed for illustrating 

the unique features of the sample introduction systems, 

mass analyzers, and vacuum systems, and for presenting 

their specifications. Various approaches for monitoring 

volatile organic compounds in cabin atmospheres were 

also reviewed. Previously, ground-based gas chromatography-mass spectrometry instruments have been used 

to identify and quantify volatile organic compounds in 

archival samples collected during the Mercury, Apollo, 

Skylab, Space Shuttle, and Mir missions. The development of direct sampling ion trap mass spectrometry and 

gas chromatography-ion mobility spectrometry has been 

discussed to illustrate their potential utility for future missions. A miniature electronic nose has been designed and 

built at the Jet Propulsion Laboratory (Pasadena, CA) to 

detect, identify, and quantify 10 common contaminants 

and relative humidity changes (232). The sensing array 

included 32 sensing films composed of polymer carbonblack composites. Event identification and quantification 

were done using the Levenberg-Marquart nonlinear least 

squares method. This electronic nose was used in a demonstration experiment aboard STS-95 (October-November, 

1998) (277), in which the electronic nose was operated 

continuously for 6 d and recorded the responses of the 

sensors to the air in the mid-deck. Air samples were collected daily and analyzed independently after the flight. 

Changes in shuttle-cabin humidity were detected and 

quantified by the electronic nose. This device was found 

to be microgravity-insensitive. 

5.4 Aircraft Engine Oils, Hydraulic Fluids, and 

Lubricants 

Many incidents of smoke/fumes in aircraft cabins 

have been linked to contamination of cabin air with 

pyrolytic products of jet engine oils, hydraulic fluids, 

and/or lubricants by leaking into ventilation air (84, 

235, 281, 283). These leaks can be subjected to 500°C or 

higher temperatures. If the origin of the smoke/fumes is 

of organic petroleum derivatives, then the smoke/fumes 

may cause a multitude of symptoms, including central 

nervous system dysfunction and mucous membrane irritation. There is a threat to safety posed by the many fluids 

and substances necessary for the operation of modern 

aircraft (222). Smoke/fume-related incidents could have 

been caused by broken seals in the engine and/or other 

associated systems, allowing these engine agents to enter 

the air compressor section and, then, contaminate the 

cabin air. To prevent such products from entering the 

cabin air, catalytic converters have been used to clean the 

air (282), but during an oil seal failure, the converters 

become overloaded, and smoke could be observed in the 

cabin. In some aircraft, the catalytic converters have been 

removed, with a claim that it improves cabin air quality. 

However, if the cabin air is contaminated, the flight crew 

is potentially exposed to the thermal breakdown products 

of the engine agents, causing the performance of the crew 

members to be impaired. Symptoms, like dizziness, nausea, 

disorientation, blurred vision, and tingling in legs and 

arms, have frequently been reported by flight crews. The 

reported symptoms are most consistent with exposures 

to CO and pyrolytic products, including volatile organic 

compounds and the organophosphate constituents of 

the oils and fluids, but the involvement of these liquids 

has not been clearly demonstrated (281). In this 1999 

study (281), to rule out the possible exposure to toxic 

elements, like lead, mercury, and thallium, a multi-elemental analysis was performed on 2 hydraulic fluids and 

3 lubricating oils that have been implicated in a number 

of air quality incidents. No significant concentrations 

of the toxic elements were found in any of the oils or 

hydraulic fluids. 

In mid-1981, several accidents involving turboprop 

aircraft occurred. It was believed that those accidents 

resulted from pilot incapacitation from toxic fumes 

introduced through the cabin pressurization system 

(235). Therefore, the thermal (300–600°C) decomposition products from aircraft petroleum-based engine 

and synthetic lubricating oils were evaluated for their 

toxicity in rats (84). The animals were exposed to smoke 

from these products, and relative toxicity was evaluated 

in terms of ti

 and td. The CO concentrations in smoke 

were measured. Based on this information, in conjunction with the animal response times, it was concluded 

that the decomposition of these oils did not produce any 

chemical species, other than CO, in quantities sufficient 

to contribute to the total toxicity.

Since bleed air is diverted from a location just prior to 

the engine combustion chamber at a temperature around 

500°C and very little is known regarding the thermal 

breakdown products of jet engine lubrication oils, 2 commercially available oils were investigated under laboratory 

conditions at 525°

C to measure the release of CO, CO2, 

nitrogen dioxide, HCN, and volatiles (282). The volatiles 

were analyzed by gas chromatography-mass spectrometry 

to establish if the neurotoxic agents, tricresyl phosphates 

(TCPs) and trimethyl propane phosphate (TMPP), were 

present or formed in the release. Although some CO2

was generated, along with CO (> 100 ppm), nitrogen 

dioxide and HCN were not detected under the analytical conditions. The presence of TCPs was confirmed in 

the bulk oils and in the volatiles, but TMPP was not 

found in these experiments. Localized condensation in 

the ventilation ducts and filters in the air conditioning 
28

packs are likely the reasons for the absence of TCPs in 

cabin air. However, the possibility of the release of pyrolysis products cannot be ruled out from the localized 

condensates in the ducts at the time of high demand of 

cabin heat, leading to mid-flight incidents (283). 

The United Kingdom’s Civil Aviation Authority (33) 

conducted an extensive study on cabin air quality involv-

ing oils and fluids. This study examined and analyzed 2 

contaminated cabin air supply ducts for the presence of 

chemical constituents and degradation products of engine 

oils, hydraulic fluids, and lubricants. These ducts were 

removed from 2 aircraft, wherein the inner surface of 

the ducts was found to be coated with black particulate 

material. Microscopic examination of this carbonaceous 

material determined that it was rich in various elements, 

such as aluminum, silicon, sulfur, and phosphorous. These 

black material deposits can be easily dislodged by gentle 

pressure. Thus, the material could potentially become 

part of the cabin and flight deck environment as solid 

aerosols. The gas chromatographic-mass spectrometric 

analyses of the airflow samples of the contaminated 

ducts suggested the presence of various short chain irritants, such as carboxylic acids, aldehydes, and ketones. 

Analyses of the solvent extracts of the carbonaceous 

material further indicated the presence of additional 

high molecular weight chemicals—for example, TCPs, 

TMPP, trimethylolpropane phosphates, and other associated esters—of relatively low volatility. It appeared 

that these molecules might have been tightly integrated 

to the carbonaceous material, suggesting that not all of 

the chemicals adsorbed onto the carbonaceous material 

could be desorbed by airflow.

It is true that the airflow samples did not contain all 

the chemicals present in the black solid coating of the 

ducts, but it does not necessarily mean that only those 

chemicals found in the airflow samples are responsible 

for the observed toxicological effects. Other chemical 

entities adsorbed onto the solid material could also 

contribute to the toxicity, if the solid material particles 

become part of the air. There is a strong potential for this 

type of situation, because the black particulate material 

present in the ducts can easily be dislodged by applying 

gentle pressure. The dislodging could also take place at 

times of high demand of cabin heat and/or by physical 

disturbances and/or stresses occurring during flights, 

particularly during taking off and landing. The ease of 

dislodging of particulate matter would also be dependent 

upon the amount of the solid matter coated inside the 

ducts—larger the size of the deposits, easier the dislodg-

ing of the deposits as the carbonaceous material particles 

would be loosely bound in the larger deposits. Hence, 

those solid particles could easily become part of the cabin 

and flight deck environment as solid aerosols. 

In such scenarios, if the cabin and flight deck occupants inhale those particles, they would be exposed to 

all the chemicals and associated entities present in the 

airflow from the ducts, as well as in the solid deposits 

of the ducts. This exposure to the mixture of chemicals 

would cause a spectrum of adverse effects—for example, 

ocular and upper respiratory irritation, nausea, vomiting, 

dizziness, pulmonary toxicity, and even delayed adverse 

effects. In this way, the solid particles would actually be 

more effective in producing localized adverse effects. 

The nature and extent of such effects would, of course, 

be dependent upon the types and amounts of chemicals 

present in the air and the duration and frequency of such 

exposures, and these parameters would vary from flight 

to flight. Therefore, the whole episode is a complex set of 

events. Also, it is not so simple to adjudicate and predict 

the toxicity caused by the constituents and the pyrolytic 

products of engine oil, hydraulic fluids, and lubricants.

In the Civil Aviation Authority study (33), the smell 

of the airflow samples was subjectively characterized for 

the odor. This qualitative approach reconfirmed that the 

odor originated from the carbonaceous material. However, 

as discussed in the report, the interrelationship cannot 

be established between the odor and the toxicity of a 

chemical. For example, some chemicals produce odor at 

very low concentrations without causing toxicity, whereas 

some chemicals have no odor but are extremely toxic. 

Toxicity of the various substances found in the carbonaceous material is described and discussed in detail with 

sufficient relevant scientific references. However, it appears 

from the report that the described toxicity is the toxicity 

exhibited by individual chemical entities. The resultant 

of the toxicity of all of the chemicals present in the black 

solid material is not clearly evident. This aspect is of particular importance, as aircraft travelers would potentially 

be exposed to chemicals, not a single chemical, from the 

black material. It is well established that the toxicity of 

individual substances differ from their mixture(s). Such 

difference would be because of the interactive effects of 

chemicals present in the mixture(s). Thus, the overall 

toxicity would be the result of additive, potentiation, 

synergistic, and/or antagonistic type of interaction(s) 

among chemicals present in the mixtures in relation to the 

toxic effects exerted by the individual components of the 

chemical mixtures (106). In other words, the chemicals 

found in the carbonaceous material may not necessarily 

be individually toxic at the found concentrations, but 

if they are mixed together at those concentrations, the 

mixture might be highly toxic. Interaction of chemicals 

would also play a crucial role in exhibiting characteristic 

odor, which may not necessarily be consistent with the 

odor exhibited by an individual chemical itself. The issue 

of the interaction of chemicals in regard to the toxicity of 
29

mixtures has apparently not been fully addressed or emphasized in the report. Because of the complexity, the best 

approach to resolve this toxicological and aviation safety 

issue would be preventive (33)—that is, to minimize oil 

leaks into bleed air and to monitor, clean, and/or replace 

air ducts. The toxicity of the oil additives that are used in 

aircraft engines should also be revisited (202). 

6 REFERENCES

1. Aviation Safety Research Act of 1988: Public Law 

100-591 [H.R. 4686]. 100th U.S. Cong., 2nd Sess., 

102 Stat. 3011 (03 November 1988).

2. ABC News. Japan-airplane fire, 0175. Retrieved 12 

May 1998 from www.abcnews.com/wire/World/

AP51298248.html.

3. Abeyratne R. Forensic aspects of the aerotoxic 

syndrome. Med Law 2002; 21(1):179–99.

4. ABFT. American Board of Forensic Toxicology 

(ABFT) laboratory accreditation program. Retrieved 25 June 2008 from www.abft.org/documents/Laboratory%20Accreditation%20Brochur

e%202006.pdf.

5. Akin A, Chaturvedi AK. Prevalence of selective 

serotonin reuptake inhibitors in pilot fatalities of 

civil aviation accidents, 1990-2001. Washington, 

DC: FAA Office of Aerospace Medicine; 2003 May. 

Report No: DOT/FAA/AM-03/07.

6. Akin A, Chaturvedi AK. Selective serotonin reuptake inhibitors in pilot fatalities of civil aviation 

accidents, 1990-2001. Aviat Space Environ Med 

2003; 74(11):1169–76.

7. AVOXimeter. AVOXimeter 4000 manual. San 

Antonio, TX: A-VOX Systems, Inc.; 2001.

8. Baar S. The micro determination of cyanide: its 

application to the analysis of whole blood. Analyst 

1966; 91(81):268–72.

9. Backman H, Haghighat F. Air quality and ocular 

discomfort aboard commercial aircraft. Optometry 

2000; 71(10):653–6.

10. Ballantyne B. The forensic diagnosis of acute 

cyanide poisoning. In: Ballantyne B, ed. Forensic 

toxicology. Bristol, UK: John Wright & Sons; 

1974:99–113.

11. Ballantyne B. Changes in blood cyanide as a function of storage time and temperature. J Forensic 

Sci Soc 1976; 16(4):305–10.

12. Ballantyne B. In vitro production of cyanide in 

normal human blood and the influence of thiocyanate and storage temperature. Clin Toxicol 1977; 

11(2):173–93.

13. Ballantyne B. Artifacts in the definition of toxicity 

by cyanides and cyanogens. Fundam Appl Toxicol 

1983; 3(5):400–8.

14. Ballantyne B. The influence of exposure route 

and species on the acute lethal toxicity and tissue 

concentrations of cyanide. In: Hayes AW, Schnell 

RC, Miya TS, eds. Developments in the science and 

practice of toxicology. Amsterdam, Netherlands: 

Elsevier Science Publishers; 1983:583–6.

15. Ballantyne B, Bright J, Williams P. Levels of cyanide in whole blood and serum following lethal 

intramuscular injection to experimental mammals. 

Med Sci Law 1970; 10(4):225–9.

16. Baselt RC. Disposition of toxic drugs and chemicals in man. 7th ed. Foster City, CA: Biomedical 

Publications; 2004:276–9.

17. Baselt RC. Disposition of toxic drugs and chemicals in man. 7th ed. Foster City, CA: Biomedical 

Publications; 2004:175–8.

18. Baud FJ, Barriot P, Toffis V, Riou B, Vicaut E, 

Lecarpentier Y, et al. Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl 

J Med 1991; 325(25):1761–6.

19. Bayer Corporation. DCA 2000 hemoglobin A1c 

reagent kit. Elkhart, IN: The Corporation; 1996.

20. Bergau L. [Radiation exposure and air quality 

aboard commercial airplanes]. Z Arztl Fortbild 

Qualitatssich 1999; 93(7):491–4.

21. Bernt A, Kerde C, Prokop O. Zur frage der verwertbarkeit von cyanidbefunden im leichenmaterial. 

Dtsch. Z. Gericht. Med 1961; 51:522–34.

22. Blackmore DJ. The bacterial production of ethyl 

alcohol. J Forensic Sci Soc 1968; 8(2):73–8.

23. Blackmore DJ. Aircraft accident toxicology: 

U.K. experience 1967-1972. Aerosp Med 1974; 

45(8):987–94.
30

24. Blanke RV. Analysis of drugs and toxic substances. 

In: Tietz NW, ed. Fundamentals of clinical chemistry. 2nd ed. Philadelphia, PA: W.B. Saunders Co.; 

1976:1116–8.

25. Blanke RV. Analysis of drugs and toxic substances. 

In: Tietz NW, ed. Fundamentals of clinical chemistry. 2nd ed. Philadelphia, PA: W.B. Saunders Co.; 

1976:1105–9.

26. Blashfield JF, Johnson RJ, eds. Above and beyond: the encyclopedia of aviation and space sciences. Chicago, IL: New Horizons Publishers, Inc.; 

1968:212.

27. Blashfield JF, Johnson RJ, eds. Above and beyond: the encyclopedia of aviation and space sciences. Chicago, IL: New Horizons Publishers, Inc.; 

1968:292.

28. Blashfield JF, Johnson RJ, eds. Above and beyond: the encyclopedia of aviation and space sciences. Chicago, IL: New Horizons Publishers, Inc.; 

1969:26.

29. Braithwaite R. Metals and anions. In: Moffat AC, 

Osselton MD, Widdop B, Galichet LY, eds. Clarke’s 

analysis of drugs and poisons in pharmaceuticals, 

body fluids and postmortem material. 3rd ed. London, UK: Pharmaceutical Press; 2004:259–78.

30. Brown TP, Shuker LK, Rushton L, Warren F, 

Stevens J. The possible effects on health, comfort 

and safety of aircraft cabin environments. J R Soc 

Health 2001; 121(3):177–84.

31. Brundrett G. Comfort and health in commercial 

aircraft: a literature review. J R Soc Health 2001; 

121(1):29–37.

32. CAA. International Cabin Water Spray Research 

Management Group: conclusions of research 

programme. London, UK: Civil Aviation Author-

ity (CAA); 1993 Jun. Report No: CAA Paper 

93012.

33. CAA. Safety Regulation Group: cabin air quality. 

West Sussex, UK: Civil Aviation Authority (CAA); 

2004 Feb. Report No: CAA Paper 2004/04.

34. Canfield D, Brink J, Johnson R, Lewis R, Dubowski

K. Clarification of ethanol-positive case using urine 

serotonin metabolite ratio. J Anal Toxicol 2007; 

31(9):592–5.

35. Canfield D, Flemig J, Hordinsky J, Birky M. Drugs 

and alcohol found in fatal civil aviation accidents 

between 1989 and 1993. Washington, DC: FAA 

Office of Aviation Medicine; 1995 Nov. Report 

No: DOT/FAA/AM-95/28.

36. Canfield DV, Chaturvedi AK, Boren HK, Veronneau SJ, White VL. Abnormal glucose levels found 

in transportation accidents. Aviat Space Environ 

Med 2001; 72(9):813–5.

37. Canfield DV, Chaturvedi AK, Boren HK, Véronneau SJH, White VL. Abnormal glucose levels 

found in transportation accidents. Washington, 

DC: FAA Office of Aviation Medicine; 2000 Jun. 

Report No: DOT/FAA/AM-00/22.

38. Canfield DV, Chaturvedi AK, Dubowski KM. 

Carboxyhemoglobin and blood cyanide concentrations in relation to aviation accidents. Aviat Space 

Environ Med 2005; 76(10):978–80.

39. Canfield DV, Chaturvedi AK, Dubowski KM. 

Interpretation of carboxyhemoglobin and cyanide 

concentrations in relation to aviation accidents. 

Washington, DC: FAA Office of Aerospace 

Medicine; 2005 May. Report No: DOT/FAA/AM05/9.

40. Canfield DV, Hordinsky J, Millett DP, Endecott B, 

Smith D. Prevalence of drugs and alcohol in fatal 

civil aviation accidents between 1994 and 1998. 

Washington, DC: FAA Office of Aviation Medicine; 

2000 Jun. Report No: DOT/FAA/AM-00/21.

41. Canfield DV, Hordinsky J, Millett DP, Endecott B, 

Smith D. Prevalence of drugs and alcohol in fatal 

civil aviation accidents between 1994 and 1998. 

Aviat Space Environ Med 2001; 72(2):120–4.

42. Canfield DV, Kupiec T, Huffine E. Postmortem 

alcohol production in fatal aircraft accidents. J 

Forensic Sci 1993; 38(4):914–7.

43. Canfield DV, Smith M, Ritter RM, Chaturvedi

AK. Preparation of carboxyhemoglobin standards 

and calculation of spectrophotometric quantitation 

constants. J Forensic Sci 1999; 44(2):409–12.

44. Canfield DV, Smith MD, Ritter RM, Chaturvedi

AK. Preparation of carboxyhemoglobin standards 

and calculation of spectrophotometric quantitation 

constants. Washington, DC: FAA Office of Aviation 

Medicine; 1998 Aug. Report No: DOT/FAA/AM98/21.
31

45. Cardeal ZL, Pradeau D, Hamon M, Abdoulaye I, 

Pailler FM, Lejeune B. New calibration method for 

gas chromatographic assay of carbon monoxide in 

blood. J Anal Toxicol 1993; 17(4):193–5.

46. Case University. Aerospace medicine; Retrieved 

23 April 2008 from www.case.edu/med/epidbio/

mphp439/Dictionary.htm.

47. CFR. Code of Federal Regulations (CFR). Title 

21—Food and drugs, Chapter II—Drug Enforcement Administration, Department of Justice, Part 

1308—Schedules of controlled substances. Wash-

ington, DC: U.S. Government Printing Office, 

2002.

48. CFR. Code of Federal Regulations (CFR). Title 

14—Aeronautics and space, Chapter I (1-1-04 Edition)—Federal Aviation Administration, Department of Transportation, Subchapter F—Air traffic 

and general operating rules, Part 91—General 

operating and flight rules, Subpart A—General: 

91.17, alcohol or drugs. Washington, DC: U.S. 

Government Printing Office, 2004.

49. CFR. Code of Federal Regulations (CFR). Title 

14—Aeronautics and space, Chapter I (1-1-04 

Edition)—Federal Aviation Administration, Department of Transportation, Subchapter G—Air 

carriers and operators for compensation or hire: 

certification and operations, Part 121—Operating 

requirements: domestic, flag, and supplemental 

operations, Appendix I—Drug testing program. 

Washington, DC: U.S. Government Printing Office, 2004.

50. Chace DH, Goldbaum LR, Lappas NT. Factors 

affecting the loss of carbon monoxide from stored 

blood samples. J Anal Toxicol 1986; 10(5):181–

9.

51. Chaturvedi AK. Biochemical and toxicological 

studies on the mixtures of three commonly-used 

herbicides in mice. Arch Environ Contam Toxicol 

1993; 24(4):449–54.

52. Chaturvedi AK. Toxicological evaluation of mixtures of ten widely used pesticides. J Appl Toxicol 

1993; 13(3):183–8.

53. Chaturvedi AK. Smoke! Oklahoma City, OK: 

FAA Civil Aerospace Medical Institute, Aerospace 

Medical Education Division. Report No: AM-400-

95/1.

54. Chaturvedi AK. The FAA’s postmortem forensic 

toxicology self-evaluated proficiency test program: the first seven years. J Forensic Sci 2000; 

45(2):422–8.

55. Chaturvedi AK, Botch SR, Canfield DV, Forster 

EM. Vitreous fluid and/or urine glucose concentrations in 1,335 civil aviation accident pilot 

fatalities [abstract]. Aviat Space Environ Med 2008; 

79(3):324–5.

56. Chaturvedi AK, Canfield DV. Role of metabolites 

in aviation forensic toxicology. Aviat Space Environ 

Med 1997; 68(3):230–3.

57. Chaturvedi AK, Cardona PS, Soper JW, Canfield 

DV. Distribution and optical purity of methamphetamine found in toxic concentration in a civil 

aviation accident pilot fatality. J Forensic Sci 2004; 

49(4):832–6.

58. Chaturvedi AK, Craft KJ, Canfield DV, Whinnery 

JE. Epidemiology of toxicological factors in civil 

aviation accident pilot fatalities, 1999-2003. Wash-

ington, DC: FAA Office of Aerospace Medicine; 

2005 Nov. Report No: DOT/FAA/AM-05/20.

59. Chaturvedi AK, Craft KJ, Canfield DV, Whinnery 

JE. Toxicological findings from 1587 civil aviation 

accident pilot fatalities, 1999-2003. Aviat Space 

Environ Med 2005; 76(12):1145–50.

60. Chaturvedi AK, Endecott BR, Ritter RM, Sanders 

DC. Variations in time-to-incapacitation and blood 

cyanide values for rats exposed to two hydrogen 

cyanide gas concentrations. Washington, DC: FAA 

Office of Aviation Medicine; 1993 May. Report 

No: DOT/FAA/AM-93-8.

61. Chaturvedi AK, Kuntz DJ, Rao NGS. Metabolic 

aspects of the toxicology of mixtures of parathion, 

toxaphene and/or 2,4-D in mice. J Appl Toxicol 

1991; 11(4):245–51.

62. Chaturvedi AK, Rao NGS, McCoy FE. A multichemical death involving caffeine, nicotine and malathion. Forensic Sci Int 1983; 23(2–3):265–75.

63. Chaturvedi AK, Sanders DC. Aircraft fires, smoke 

toxicity, and survival: an overview. Washington, 

DC: FAA Office of Aviation Medicine; 1995 Feb. 

Report No: DOT/FAA/AM-95/8.

64. Chaturvedi AK, Sanders DC. Aircraft fires, smoke 

toxicity, and survival. Aviat Space Environ Med 

1996; 67(3):275–8.
32

65. Chaturvedi AK, Sanders DC, Endecott BR, Ritter 

RM. Exposures to carbon monoxide, hydrogen cyanide and their mixtures: interrelationship between 

gas exposure concentration, time to incapacitation, 

carboxyhemoglobin and blood cyanide in rats. J 

Appl Toxicol 1995; 15(5):357–63.

66. Chaturvedi AK, Singh G, Rao NGS, Parker TM. 

Toxicological evaluation of a poisoning attributed to 

ingestion of malathion insect spray and correlation 

with in vitro inhibition of cholinesterases. Hum 

Toxicol 1989; 8(1):11–8.

67. Chaturvedi AK, Smith DR, Canfield DV. Blood 

carbon monoxide and cyanide concentrations in 

the fatalities of fire and non-fire associated civil 

aviation accidents, 1991-1998. Washington, DC: 

FAA Office of Aviation Medicine; 2000 Feb. Report 

No: DOT/FAA/AM-00/9.

68. Chaturvedi AK, Smith DR, Canfield DV. Blood 

carbon monoxide and hydrogen cyanide concentrations in the fatalities of fire and non-fire associated 

civil aviation accidents, 1991-1998. Forensic Sci

Int 2001; 121(3):183–8.

69. Chaturvedi AK, Smith DR, Soper JW, Canfield 

DV, Whinnery JE. Characteristics and toxicological processing of postmortem pilot specimens from 

fatal civil aviation accidents. Aviat Space Environ 

Med 2003; 74(3):252–9.

70. Chaturvedi AK, Vu NT, Ritter RM, Canfield DV. 

DNA typing as a strategy for resolving issues relevant to forensic toxicology. J Forensic Sci 1999; 

44(1):189–92.

71. Clark G. Problems in aerial application: a comparison of the acute effects of endrin and carbon 

tetrachloride on the livers of rats and of the residual 

effects one month after poisoning. Washington, 

DC: FAA Office of Aviation Medicine; 1966 Jul. 

Report No: FAA-AM-66-34.

72. Clark G. Problems in aerial application: a comparison of the effects of dieldrin poisoning in 

cold-adapted and room-temperature mammals. 

Washington, DC: FAA Office of Aviation Medicine; 

1966 Apr. Report No: FAA-AM-66-5.

73. CNN. 11 Dead in Montreal plane crash; Retrieved 

18 June 1998 from cnn.com/WORLD/americas/9806/18/montreal.plane.crash.02.reut/index.

html.

74. CO-Oximeter. Operator’s manual IL282 CO-Ox-

imeter. Lexington, MA: Instrumentation Laboratory, Inc.; 1978.

75. Corry JE. A review. Possible sources of ethanol 

ante- and post-mortem: its relationship to the 

biochemistry and microbiology of decomposition. 

J Appl Bacteriol 1978; 44(1):1–56.

76. Crane CR, Endecott BR, Sanders DC, Abbott JK. 

Electrical insulation fire characteristics - volume 

II: toxicity. Washington, DC: U.S. Department 

of Transportation/Urban Mass Transportation Administration, Office of Technology Development 

and Deployment, Office of Rail and Construction 

Technology; 1979 Mar. Report No: UMTA-MA06-0025-79-2, II.

77. Crane CR, Sanders DC, Abbot JK. A comparison 

of three serum cholinesterase methods. Washington, 

DC: FAA Office of Aviation Medicine; 1970 Aug. 

Report No: FAA-AM-70-13.

78. Crane CR, Sanders DC, Abbot JK. Studies on the 

storage stability of human blood cholinesterases: I. 

Washington, DC: FAA Office of Aviation Medicine; 

1970 Jan. Report No: FAA-AM-70-4.

79. Crane CR, Sanders DC, Abbot JK. A comparison 

of serum cholinesterase methods: II. Washington, 

DC: FAA Office of Aviation Medicine; 1972 Mar. 

Report No: FAA-AM-72-12.

80. Crane CR, Sanders DC, Endecott BR. Inhalation 

toxicology: IX. Times-to-incapacitation for rats 

exposed to carbon monoxide alone, to hydrogen 

cyanide alone, and to mixtures of carbon monoxide 

and hydrogen cyanide. Washington, DC: FAA Office of Aviation Medicine; 1989 Jan. Report No: 

DOT/FAA/AM-89/4.

81. Crane CR, Sanders DC, Endecott BR. Inhalation 

toxicology: X. Times to incapacitation for rats 

exposed continuously to carbon monoxide, acrolein, and to carbon monoxide-acrolein mixtures. 

Washington, DC: FAA Office of Aviation Medicine; 

1990 Dec. Report No: DOT/FAA/AM-90/15.

82. Crane CR, Sanders DC, Endecott BR. Incapacitation in the laboratory rat induced by inhalation 

of carbon monoxide-acrolein mixtures. J Fire Sci

1992; 10(2):133–59.
33

83. Crane CR, Sanders DC, Endecott BR, Abbott JK. 

Combustibility of electrical wire and cable for rail 

rapid transit systems - Volume II: Toxicity. Washington, DC: U.S. Department of Transportation/Urban 

Mass Transportation Administration, Office of 

Technology Development and Deployment, Office 

of Rail and Construction Technology; 1983 May. 

Report No: DOT-TSC-UMTA-83-4, II.

84. Crane CR, Sanders DC, Endecott BR, Abbott JK. 

Inhalation toxicology: III. Evaluation of thermal 

degradation products from aircraft and automobile 

engine oils, aircraft hydraulic fluid, and mineral oil. 

Washington, DC: FAA Office of Aviation Medicine; 

1983 Apr. Report No: FAA-AM-83/12.

85. Crane CR, Sanders DC, Endecott BR, Abbott JK. 

Inhalation toxicology: IV. Times to incapacitation and death for rats exposed continuously to 

atmospheric hydrogen chloride gas. Washington, 

DC: FAA Office of Aviation Medicine; 1985 May. 

Report No: FAA-AM-85/4.

86. Crane CR, Sanders DC, Endecott BR, Abbott JK. 

Inhalation toxicology: VI. Evaluation of the relative 

toxicity of thermal decomposition products from 

nine aircraft panel materials. Washington, DC: FAA 

Office of Aviation Medicine; 1986 Feb. Report No: 

DOT/FAA/AM-86/3.

87. Crane CR, Sanders DC, Endecott BR, Abbott JK. 

Inhalation toxicology: VII. Times to incapacitation and death for rats exposed continuously to 

atmospheric acrolein vapor. Washington, DC: FAA 

Office of Aviation Medicine; 1986 May. Report 

No: DOT/FAA/AM-86/5.

88. Crane CR, Sanders DC, Endecott BR, Abbott 

JK, Smith PW. Inhalation toxicology: I. Design of 

a small-animal system; II. Determination of the 

relative toxic hazards of 75 aircraft cabin materials. 

Washington, DC: FAA Office of Aviation Medicine; 

1977 Mar. Report No: DOT/FAA-AM-77/9.

89. Cullen SA, Hill IR. Aviation pathology and toxicology. In: Rainford DJ, Gradwell DP, eds. Ernsting’s 

aviation medicine. 4th ed. London, UK: Hodder 

Arnold; 2006:517–32.

90. Curry AS. Cyanide poisoning. Acta Pharmacol 

Toxicol (Copenh) 1963; 20:291–4.

91. Curry AS. Poison detection in human organs. 4th ed. 

Springfield, IL: Charles C Thomas; 1988:210–2.

92. Curry AS, Price DE, Rutter ER. The production of 

cyanide in post mortem material. Acta Pharmacol 

Toxicol (Copenh) 1967; 25(3):339–44.

93. Daugherty JW, Lacey DE, Korty P. Problems in 

aerial application: I. some biochemical effects of 

lindane and dieldrin on vertebrates. Oklahoma City, 

OK: FAA Civil Aeromedical Research Institute; 

1962 May. Report No: FAA-AM-62-10.

94. Daugherty JW, Lacey DE, Korty P. Problems in 

aerial application: II. Effects of chlorinated hydrocarbons on substrate-linked phosphorylation. Oklahoma City, OK: FAA Civil Aeromedical Research 

Institute; 1963 Mar. Report No: FAA-AM-63-4.

95. Dechow M, Sohn H, Steinhanses J. Concentrations of selected contaminants in cabin air of airbus 

aircrafts. Chemosphere 1997; 35(1–2):21–31.

96. DeHart RL. Health issues of air travel. Annu Rev 

Public Health 2003; 24:133–51.

97. Dille JR, Mohler SR. Drug and toxic hazards in 

general aviation. Washington, DC: FAA Office of 

Aviation Medicine; 1968 Sep. Report No: FAAAM-68-16.

98. Dille JR, Morris EW. Human factors in general 

aviation accidents. Washington, DC: FAA Office 

of Aviation Medicine; 1966 Jul. Report No: FAAAM-66-27.

99. Dille JR, Morris EW. Human factors in general aviation accidents. Aerosp Med 1967; 38(10):1063–6.

100. Dille JR, Smith PW. Central nervous system effects 

of chronic exposure to organophosphate insecticides. Oklahoma City, OK: FAA Civil Aeromedical 

Research Institute; 1963 Oct. Report No: FAAAM-63-24.

101. Dille JR, Smith PW. Central nervous system effects 

of chronic exposure to organophosphate insecticides. Aerosp Med 1964; 35:474–8.

102. DOT. Department of Transportation (DOT), Federal Aviation Administration, Antidrug and alcohol 

misuse prevention programs for personnel engaged 

in specified aviation activities. Federal Register 1999 

Dec; 64(232):67965–6.
34

103. DOT. Aircraft accident and incident notification, investigation, and reporting. U.S. Department of Transportation (DOT), Federal Aviation 

Administration, Order No. 8020.11B, Chapter 

4—Aircraft accident investigation responsibilities, 

Section 3—Office of Aviation Medicine, Paragraph 

137—Civil Aeromedical Institute responsibilities, 

Washington, DC (16 August 2000).

104. Douglas TA. The determination of carbon monoxide in blood. Ann Occup Hyg 1962; 5:211–6.

105. Dunn WA, Siek TJ. A rapid, sensitive, and specific 

screening technique for the determination of cyanide. J Anal Toxicol 1990; 14(4):256.

106. Eaton DL, Klaassen CD. Principles of toxicology. In: Klaassen CD, Amdur MO, Doull J, eds. 

Casarett & Doull’s toxicology: The basic science 

of poisons. 5th ed. New York, NY: McGraw-Hill; 

1996:13−33.

107. Eckert WG. The medicolegal and forensic aspects of fires. Am J Forensic Med Pathol 1981; 

2(4):347–57.

108. Ecobichon DJ. Chemical management of forest 

pest epidemics: A case study. Biomed Environ Sci

1990; 3(2):217–39.

109. Ecobichon DJ. Toxic effects of pesticides. In: Klaassen CD, Amdur MO, Doull J, eds. Casarett & 

Doull’s toxicology: The basic science of poisons. 5th 

ed. New York, NY: McGraw-Hill; 1996:643−89.

110. Eilers RJ. Notification of final adoption of an 

international method and standard solution for 

hemoglobinometry specifications for preparation 

of standard solution. Am J Clin Pathol 1967; 

47(2):212–4.

111. Emerson TE, Jr., Brake CM, Hinshaw LB. Mechanism of action of the insecticide endrin. Oklahoma 

City, OK: FAA Civil Aeromedical Research Institute; 1963 Aug. Report No: FAA-AM-63-16.

112. Endecott BR, Sanders DC, Chaturvedi AK. Simultaneous gas-chromatographic determination 

of four toxic gases generally present in combustion 

atmospheres. Washington, DC: FAA Office of 

Aviation Medicine; 1994 Sep. Report No: DOT/

FAA/AM-94/18.

113. Endecott BR, Sanders DC, Chaturvedi AK. Simultaneous gas chromatographic determination 

of four toxic gases generally present in combustion 

atmospheres. J Anal Toxicol 1996; 20(3):189–94.

114. EUROCAE. Minimum operational performance 

specification for passenger protective breathing 

equipment. Paris, France: The European Organisation for Civil Aviation Equipment (EUROCAE); 

1991 Apr. Report No: ED-65.

115. Fairbanks VF. Hemoglobin, hemoglobin derivatives, and myoglobin. In: Tietz NW, ed. Fundamentals of clinical chemistry. 2nd ed. Philadelphia, 

PA: W.B. Saunders Co.; 1976:411–4.

116. Fechner GG, Gee DJ. Study on the effects of heat 

on blood and on the post-mortem estimation of 

carboxyhaemoglobin and methaemoglobin. Forensic Sci Int 1989; 40(1):63–7.

117. Feldstein M, Klendshoj NC. The determination 

of volatile substances by microdiffusion analysis. J 

Forensic Sci 1957; 2:39–58.

118. Felscher D, Wulfmeyer M. A new specific method 

to detect cyanide in body fluids, especially whole 

blood, by fluorimetry. J Anal Toxicol 1998; 

22(5):363–6.

119. Fenner OH. Chemical and environmental properties of plastics and elastomers. In: Harper CA, ed. 

Handbook of plastics and elastomers. New York, 

NY: McGraw-Hill Book Company; 1975:1–81.

120. Fowler PR, McKenzie JM. Problems in aerial application: detection of mild poisoning by organophosphorus pesticides using an automated method 

for cholinesterase activity. Washington, DC: FAA 

Office of Aviation Medicine; 1967 Apr. Report No: 

FAA-AM-67-5.

121. Freireich A, Landau D, Dubowski KM, Jain NC. 

Carbon Monoxide: Type B procedure. In: Sunshine 

I, ed. Methodology for analytical toxicology. Boca 

Raton, FL: CRC Press, Inc.; 1975:67–9.

122. Fulton HB, Jr. A pilot’s guide to cabin air quality and 

fire safety. N Y State J Med 1985; 85(7):384–8.

123. Gad SC. The toxicity of smoke and combustion 

gases. In: Gad SC, Anderson RC, eds. Combustion toxicology. Boca Raton, FL: CRC Press, Inc.; 

1990:63–80.

124. Galea ER, Owen M, Lawrence PJ. Computer modelling of human behaviour in aircraft fire accidents. 

Toxicology 1996; 115(1–3):63–78.

125. Gallo MA. History and scope of toxicology. In: 

Klaassen CD, Amdur MO, Doull J, eds. Casarett & 

Doull’s toxicology: The basic science of poisons. 5th 

ed. New York, NY: McGraw-Hill; 1996:3−11.
35

126. GAO. Aviation safety: Slow progress in making 

aircraft cabin interiors fireproof. Washington, DC: 

U.S. General Accounting Office (GAO); 1993 Jan. 

Report No: GAO/RCED-93-37.

127. Ginestet A, Pugnet D, Rowley J, Bull K, Yeomans 

H. Development of a new photocatalytic oxidation air filter for aircraft cabin. Indoor Air 2005; 

15(5):326–34.

128. Gossel TA, Bricker JD. Principles of clinical 

toxicology. 3rd ed. New York, NY: Raven Press; 

1994:147–78.

129. Gossel TA, Bricker JD. Principles of clinical 

toxicology. 3rd ed. New York, NY: Raven Press; 

1994:109–34.

130. Griffin BR. A sensitive method for the routine 

determination of carbon monoxide in blood using 

flame ionization gas chromatography. J Anal Toxicol 

1979; 3:102–4.

131. Guilbault GG, Kramer DN. Ultra sensitive, specific 

method for cyanide using p-nitrobenzaldehyde and 

o-dinitrobenzene. Anal Chem 1966; 38:834–6.

132. Haditsch M. [Flying fitness of patients with infections]. Wien Med Wochenschr 2002; 152(17–

18):469–72.

133. Hagan RL, Helander A. Urinary 5-hydroxytryptophol following acute ethanol consumption: Clinical 

evaluation and potential aviation applications. Aviat 

Space Environ Med 1997; 68(1):30–4.

134. Harding R. Cabin air quality in aircraft. BMJ 1994; 

308(6926):427–8.

135. Harper CA. Fundamentals of plastics and elastomers. In: Harper CA, ed. Handbook of plastics and 

elastomers. New York, NY: McGraw-Hill Book 

Company; 1975:1–121.

136. Hartzell GE. Combustion of materials. In: Hartzell GE, ed. Advances in Combustion Toxicology. 

Lancaster, PA: Technomic Publishing Co., Inc.; 

1989:1–7.

137. Hartzell GE. Understanding of hazards to humans. 

In: Hartzell GE, ed. Advances in Combustion 

Toxicology. Lancaster, PA: Technomic Publishing 

Co., Inc.; 1989:19–37.

138. Hartzell GE. Overview of combustion toxicology. 

Toxicology 1996; 115(1–3):7–23.

139. Hartzell GE, Switzer WG, Priest DN. Modeling of 

toxicological effects of fire gases: V. Mathematical 

modeling of intoxication of rats by combined carbon 

monoxide and hydrogen cyanide atmospheres. In: 

Hartzell GE, ed. Advances in combustion toxicology. Lancaster, PA: Technomic Publishing Co., Inc.; 

1989:35–47.

140. Helliker K. Federal agency says urine-alcohol test 

isn’t totally reliable. Thursday, 05 October 2006. 

The Wall Street Journal – [information provided 

by postgazette. com] 2006.

141. Hetrick SM, Gould WD, Christensen DE. Inflight cabin ozone aboard long duration C-5 airlift 

missions: A historical issue revisited. Aviat Space 

Environ Med 2000; 71(4):408–14.

142. Higgins EA, Fiorica V, Thomas AA, Davis HV. The 

acute toxicity of brief exposures to HF, HCl, NO2

and HCN singly and in combination with CO. 

Washington, DC: FAA Office of Aviation Medicine; 

1971 Nov. Report No: FAA-AM-71-41.

143. Hill IR. Toxicological findings in fatal aircraft 

accidents in the United Kingdom. Am J Forensic 

Med Pathol 1986; 7(4):322–6.

144. Hinshaw LB, Emerson TE, Jr., Rieger JA, Jr., Stavinoha WB, Solomon LA, Fiorica V, et al. Problems 

in aerial application: I.— V. Washington, DC: FAA 

Office of Aviation Medicine; 1966 Jun. Report No: 

FAA-AM-66-11.

145. Hocking MB. Indoor air quality: Recommendations relevant to aircraft passenger cabins. Am Ind 

Hyg Assoc J 1998; 59(7):446–54.

146. Hocking MB. Passenger aircraft cabin air quality: 

Trends, effects, societal costs, proposals. Chemosphere 2000; 41(4):603–15.

147. Hocking MB. Trends in cabin air quality of commercial aircraft: Industry and passenger perspectives. Rev Environ Health 2002; 17(1):1–49.

148. Hoiseth G, Bernard JP, Stephanson N, Normann 

PT, Christophersen AS, Morland J, et al. Comparison between the urinary alcohol markers EtG, EtS, 

and GTOL/5-HIAA in a controlled drinking experiment. Alcohol Alcohol 2008; 43(2):187–91.

149. Hoiseth G, Karinen R, Johnsen L, Normann PT, 

Christophersen AS, Morland J. Disappearance 

of ethyl glucuronide during heavy putrefaction. 

Forensic Sci Int 2008; 176(2–3):147–51.
36

150. Johnson RD, Lewis RJ. Identification of sildenafil 

(Viagra®) and its Metabolite (UK 103,320) in six 

aviation fatalities. Washington, DC: FAA Office 

of Aerospace Medicine; 2006 Feb. Report No: 

DOT/FAA/AM-06/3.

151. Johnson RD, Lewis RJ, Angier MK. The distribution of fluoxetine in h)uman fluids and tissues. J 

Anal Toxicol 2007; 31(7):409–14.

152. Johnson RD, Lewis RJ, Angier MK. The postmortem distribution of vardenafil (Levitra) in 

an aviation accident victim with an unusually 

high blood concentration. J Anal Toxicol 2007; 

31(6):328–33.

153. Johnson RD, Lewis RJ, Canfield DV, Blank CL. Accurate assignment of ethanol origin in postmortem 

urine: Liquid chromatographic-mass spectrometric 

determination of serotonin metabolites. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 

805(2):223–34.

154. Johnson RD, Lewis RJ, Canfield DV, Dubowski

KM, Blank CL. Utilizing the urinary 5-HTOL/5-

HIAA ratio to determine ethanol origin in civil 

aviation accident victims. J Forensic Sci 2005; 

50(3):670–5.

155. Jones JT, Jones MR, Plate CA, Lewis D. Ethyl 

glucuronide and ethyl sulfate concentrations following inhalation of ethanol vapor. United States 

Drug Testing Laboratories, Inc, 1700 South Mount 

Prospect Road, Des Plaines, IL 60018 (USDTL 

Research Monograph 2006.03), 2006.

156. Kaplan HL, Hartzell GE. Modeling of toxicological effects of fire gases: I. Incapacitating effects of 

narcotic fire gases. J Fire Sci 1984; 2:286–305.

157. Katsumata Y, Aoki M, Oya M, Suzuki O, Yada S. 

Simultaneous determination of carboxyhemoglobin 

and methemoglobin in victims of carbon monoxide 

poisoning. J Forensic Sci 1980; 25(3):546–9.

158. Klaassen CD. Nonmetallic environmental toxicants: Air pollutants, solvents and vapors, and 

pesticides. In: Hardman JG, Limbird LE, Gilman 

AG, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 10th ed. New York, NY: 

McGraw-Hill; 2001:1877–902.

159. Klette K, Levine B, Springate C, Smith ML. Toxicological findings in military aircraft fatalities from 

1986-1990. Forensic Sci Int 1992; 53(2):143–8.

160. Kugelberg FC, Jones AW. Interpreting results 

of ethanol analysis in postmortem specimens: A 

review of the literature. Forensic Sci Int 2007; 

165(1):10–29.

161. Kuhlman JJ, Jr., Levine B, Smith ML, Hordinsky 

JR. Toxicological findings in Federal Aviation Administration general aviation accidents. J Forensic 

Sci 1991; 36(4):1121–8.

162. Kuntz DJ, Rao NGS, Berg IE, Khattree R, 

Chaturvedi AK. Toxicity of mixtures of parathion, 

toxaphene and/or 2,4-D in mice. J Appl Toxicol 

1990; 10(4):257–66.

163. Kupfer DM, Chaturvedi AK, Canfield DV, Roe BA. 

PCR-based identification of postmortem microbial 

contaminants--a preliminary study. J Forensic Sci

1999; 44(3):592–6.

164. Kupiec TC, Chaturvedi AK. Stereochemical determination of selegiline metabolites in postmortem biological specimens. J Forensic Sci 1999; 

44(1):222–6.

165. Lacefield DJ, Roberts PA, Blossom CW. Toxicological findings in fatal civil aviation accidents, fiscal 

years 1968-1974. Aviat Space Environ Med 1975; 

46(8):1030–2.

166. Lacefield DJ, Roberts PA, Blossom CW. Agricultural aviation versus other general aviation: Toxicological findings in fatal accidents. Washington, 

DC: FAA Office of Aviation Medicine. Report No: 

FAA-AM-78-31.

167. Landrock AH. Handbook of plastics flammability 

and combustion toxicology: Principles, materials, 

testing, safety, and smoke inhalation effects. Park 

Ridge, NJ: Noyes Publications; 1983:18–22.

168. Lauwerys RR. Occupational toxicology. In: Klaassen 

CD, Amdur MO, Doull J, eds. Casarett & Doull’s 

toxicology: The basic science of poisons. 5th ed. 

New York, NY: McGraw-Hill; 1996:987−1009.

169. Leder K, Newman D. Respiratory infections during 

air travel. Intern Med J 2005; 35(1):50–5.

170. Levin BC, Rechani PR, Gurman JL, Landron F, 

Clark HM, Yoklavich MF, et al. Analysis of carboxyhemoglobin and cyanide in blood from victims 

of the Dupont Plaza Hotel fire in Puerto Rico. J 

Forensic Sci 1990; 35(1):151–68.
37

171. Lewis MF, Mertens HW, Steen JA. Behavioral 

changes from chronic exposure to pesticides used 

in aerial application: Effects of phosdrin on the 

performance of monkeys and pigeons on variable 

interval reinforcement schedules. Washington, DC: 

FAA Office of Aviation Medicine; 1972 Aug. Report 

No: FAA-AM-72-29.

172. Lewis RJ, Johnson RD, Angier MK, Vu NT. Ethanol 

formation in unadulterated postmortem tissues. 

Forensic Sci Int 2004; 146(1):17–24.

173. Lewis RJ, Johnson RD, Blank CL. Quantitative 

determination of sildenafil (Viagra) and its metabolite (UK-103,320) in fluid and tissue specimens 

obtained from six aviation fatalities. J Anal Toxicol 

2006; 30(1):14–20.

174. Lewis RJ, Johnson RD, Canfield DV. An accurate 

method for the determination of carboxyhemoglobin in postmortem blood using GC-TCD. J Anal 

Toxicol 2004; 28(1):59–62.

175. Lewis RJ, Johnson RD, Angier MK. The distribution of fluoxetine and norfluoxetine in postmortem 

fluids and tissues. Washington, DC: FAA Office 

of Aerospace Medicine; 2007 Jun. Report No: 

DOT/FAA/AM-07/15.

176. Lewis RJ, Johnson RD, Southern TL, Canfield DV. 

Distribution of butalbital in postmortem tissues 

and fluids from non-overdose cases. J Anal Toxicol 

2003; 27(3):145–8.

177. Li G, Baker SP. Crashes of commuter aircraft and 

air taxis. What determines pilot survival? J Occup 

Med 1993; 35(12):1244–9.

178. Lindgren T, Norback D. Cabin air quality: Indoor 

pollutants and climate during intercontinental 

flights with and without tobacco smoking. Indoor 

Air 2002; 12(4):263–72.

179. Lindgren T, Norback D. Health and perception of 

cabin air quality among Swedish commercial airline 

crew. Indoor Air 2005; 15 Suppl 10:65–72.

180. Lindgren T, Norback D, Andersson K, Dammstrom 

BG. Cabin environment and perception of cabin 

air quality among commercial aircrew. Aviat Space 

Environ Med 2000; 71(8):774–82.

181. Lindgren T, Norback D, Wieslander G. Perception 

of cabin air quality in airline crew related to air 

humidification, on intercontinental flights. Indoor 

Air 2007; 17(3):204–10.

182. Loomis TA. Essentials of toxicology. 3rd ed. Philadelphia, PA: Lea & Febiger; 1978:1–12.

183. Lundquist P, Rammer L, Sorbo B. The role of 

hydrogen cyanide and carbon monoxide in fire 

casualties: A prospective study. Forensic Sci Int 

1989; 43(1):9–14.

184. Maehly AC, Swensson A. Cyanide and thiocyanate 

levels in blood and urine of workers with low-grade 

exposure to cyanide. Int Arch Arbeitsmed 1970; 

27(3):195–209.

185. Mayes RW. The toxicological examination of the 

victims of the British Air Tours Boeing 737 accident at Manchester in 1985. J Forensic Sci 1991; 

36(1):179–84.

186. McAuley F, Reive DS. Rapid quantitation of cyanide 

in blood by gas chromatography. J Anal Toxicol 

1983; 7(5):213–5.

187. McKenna JT. Blaze pierced ValuJet cabin: Evidence 

points to cargo fire that filled passenger cabin with 

smoke and toxic fumes before impact. Aviat Week 

Space Technol 1996; 144(24):25–6.

188. McMillan DE, Svoboda AC, IV. The role of erythrocytes in cyanide detoxification. J Pharmacol Exp 

Ther 1982; 221(1):37–42.

189. Meyer E. Chemistry of hazardous materials. 

Englewood Cliffs, NJ: Prentice-Hall, Inc.; 

1977:78–99.

190. Meyers RAM, Thom SR. Carbon monoxide and 

cyanide poisoning. In: Kindwall EP, ed. Hyperbaric 

medicine practice. Chapter 18, 1st ed. Flagstaff, 

AZ: Best Publishing Co.; 1995:344–72.

191. Mohler SR, Harper CR. Protecting the Ag pilot. 

Washington, DC: FAA Office of Aviation Medicine; 

1966 Sep. Report No: FAA-AM-66-30.

192. Morgan RL, Isom GE, Way JL. Resolution of 

thiosulfate interference in cyanide determination. 

Toxicol Appl Pharmacol 1979; 50(2):323–8.

193. Moriya F, Hashimoto Y. Potential for error when 

assessing blood cyanide concentrations in fire victims. J Forensic Sci 2001; 46(6):1421–5.

194. Moriya F, Hashimoto Y. Chemical factors affecting 

the interpretation of blood cyanide concentrations 

in fire victims. Leg Med (Tokyo) 2003; 5 Suppl 1:

S113–7.
38

195. Musshoff F. Chromatographic methods for the 

determination of markers of chronic and acute alcohol consumption. J Chromatogr B Analyt Technol 

Biomed Life Sci 2002; 781(1–2):457–80.

196. Nagda NL, Hodgson M. Low relative humidity 

and aircraft cabin air quality. Indoor Air 2001; 

11(3):200–14.

197. Nagda NL, Koontz MD. Review of studies on flight 

attendant health and comfort in airliner cabins. 

Aviat Space Environ Med 2003; 74(2):101–9.

198. Nagda NL, Rector HE. A critical review of reported 

air concentrations of organic compounds in aircraft 

cabins. Indoor Air 2003; 13(3):292–301.

199. National Library of Medicine. Aerospace medicine; 

Retrieved 23 April 2008 from www.ncbi.nlm.nih.

gov/sites/entrez?db=mesh.

200. Nelson GL. Carbon monoxide and fire toxicity: A 

review and analysis of recent work. Fire Technology 

1998; 34:38–58.

201. Nelson GL, Canfield DV, Larsen JB. Carbon 

monoxide and fatalities: A case study of toxicity 

in man. In: Hirschler MM, Debanne SM, Larsen 

JB, Nelson GL, eds. Carbon monoxide and human 

lethality: fire and non-fire studies. London, UK: 

Elsevier Applied Science; 1993:179–96.

202. Nicholson AN, Cummin AR, Giangrande PL. The 

airline passenger: Current medical issues. Travel 

Med Infect Dis 2003; 1(2):94–102.

203. Nohl H, Stolze K. Formation of methemoglobin 

and free radicals in erythrocytes. Met Ions Biol Syst 

1999; 36:289–307.

204. NTSB. Aircraft accident report: Capitol International Airways, Inc., DC-8-63F, N4909C, Anchorage, Alaska, November 27, 1970. Washington, DC: 

U.S. National Transportation Safety Board (NTSB). 

Report No: NTSB-AAR-72-12, File No: 1-0025, 

1972.

205. O’Neal CL, Poklis A. Postmortem production of 

ethanol and factors that influence interpretation: 

A critical review. Am J Forensic Med Pathol 1996; 

17(1):8–20.

206. Odoul M, Fouillet B, Nouri B, Chambon R, Chambon P. Specific determination of cyanide in blood 

by headspace gas chromatography. J Anal Toxicol 

1994; 18(4):205–7.

207. Packham SC, Hartzell GE. Fundamentals of combustion toxicology in fire hazard assessment. J Test 

Eval 1981; 9:341–7.

208. Pakhomova AA, Mukhamedieva LN, Mikos KN. 

[Air quality monitoring on the International Space 

Station]. Aviakosm Ekolog Med 2006; 40(2):46–

9.

209. Palmer PT, Limero TF. Mass spectrometry in the 

U.S. space program: Past, present, and future. J Am 

Soc Mass Spectrom 2001; 12(6):656–75.

210. Patterson RE, Rayman RB. Aerospace air pollution issues. Otolaryngol Head Neck Surg 1996; 

114(2):277–80.

211. Pearson DW, Clark G, Moore CM. A comparison 

of the behavioral effects of various levels of chronic 

disulfoton poisoning. Washington, DC: FAA Office of Aviation Medicine; 1969 Oct. Report No: 

FAA-AM-69-19.

212. Petajan JH, Voorhees KJ, Packham SC, Baldwin 

RC, Einhorn IN, Grunnet ML, et al. Extreme toxic-

ity from combustion products of a fire-retarded polyurethane foam. Science 1975; 187(4178):742–4.

213. Proctor P. In-flight smoke and fire rare, but deadly. 

Aviat Week Space Technol 1996; 144(21):29.

214. Purser DA. Toxicity assessment of combustion 

products. In: DiNenno PJ, ed. The SFPE handbook 

of fire protection engineering. 3rd ed. Quincy, MA: 

National Fire Protection Association; 2002:2/83–

2/171.

215. Purser DA, Berrill KR. Effects of carbon monoxide 

on behavior in monkeys in relation to human fire hazard. Arch Environ Health 1983; 38(5):308–15.

216. Purser DA, Grimshaw P, Berrill KR. Intoxication 

by cyanide in fires: A study in monkeys using 

polyacrylonitrile. Arch Environ Health 1984; 

39(6):394–400.

217. Rayman. Aircraft cabin air quality and bills in 

Congress [editorial: executive director’s column]. 

Aviat Space Environ Med 2001; 72(11):1055.

218. Rayman. National Academy of Sciences report 

on cabin air quality [editorial: executive director’s column]. Aviat Space Environ Med 2002; 

73(3):319.
39

219. Rayman RB. Passenger safety, health, and comfort: A review. Aviat Space Environ Med 1997; 

68(5):432–40.

220. Rayman RB. Aircraft cabin air quality: An overview 

[correction of overview]. Uchu Koku Kankyo Igaku 

2001; 38(1):9–15.

221. Rayman RB. Cabin air quality: An overview. Aviat 

Space Environ Med 2002; 73(3):211–5.

222. Rayman RB, McNaughton GB. Smoke/fumes 

in the cockpit. Aviat Space Environ Med 1983; 

54(8):738–40.

223. Reins DA, Holmes DD, Hinshaw LB. Acute and 

chronic effects of the insecticide endrin on renal 

function and renal hemodynamics. Oklahoma City, 

OK: FAA Civil Aeromedical Research Institute; 

1963 Oct. Report No: FAA-AM-63-26.

224. Repace J. Flying the smoky skies: Secondhand 

smoke exposure of flight attendants. Tob Control 

2004; 13 Suppl 1:i8–19.

225. Revzin AM. Some acute and chronic effects of 

endrin on the brain. Washington, DC: FAA Office 

of Aviation Medicine; 1970 Jul. Report No: FAAAM-70-11.

226. Revzin AM. Subtle changes in brain functions 

produced by single doses of mevinphos (phosdrin). 

Washington, DC: FAA Office of Aviation Medicine; 

1973 Feb. Report No: FAA-AM-73-3.

227. Revzin AM. Transient blindness due to the combined effects of mevinphos and atropine. Washington, DC: FAA Office of Aviation Medicine; 1973 

Feb. Report No: FAA-AM-73-4.

228. Rieders F. Cyanide: Type A procedure. In: Sunshine 

I, ed. Methodology for analytical toxicology. Boca 

Raton, FL: CRC Press, Inc.; 1975:114–5.

229. Rieders F. Cyanide: Type A procedure. In: Sunshine 

I, ed. Methodology for analytical toxicology. Boca 

Raton, FL: CRC Press, Inc.; 1975:113–4.

230. Rodkey FL, Hill TA, Pitts LL, Robertson RF. 

Spectrophotometric measurement of carboxyhemoglobin and methemoglobin in blood. Clin Chem 

1979; 25(8):1388–93.

231. Ryan LC, Endecott BR, Hanneman GD, Smith 

DR. Effects of an organophosphorus pesticide on 

reproduction in the rat. Washington, DC: FAA 

Office of Aviation Medicine; 1970 Jan. Report No: 

FAA-AM-70-3.

232. Ryan MA, Zhou H, Buehler MG, Manatt KS, 

Mowrey VS, Jackson SP, et al. Monitoring space 

shuttle air quality using the Jet Propulsion Laboratory electronic nose. IEEE Sens J 2004; 4(3):337–

47.

233. Salazar GJ, Antuñano MJ. Alcohol and flying: a 

deadly combination. Oklahoma City, OK: FAA 

Civil Aerospace Medical Institute, Aerospace 

Medical Education Division. Report No: AM-400-

94/2.

234. Salomone J, 3rd, Sohn AP, Ritzlin R, Gauthier JH, 

McCarty V. Correlations of injury, toxicology, and 

cause of death to Galaxy Flight 203 crash site. J 

Forensic Sci 1987; 32(5):1403–15.

235. Sanders DC. Combustion toxicology research in 

the Biochemistry Research Unit, CAMI, 1970-

1992. In: Collins WE, Wayda ME, eds. Index of 

FAA Office of Aerospace Medicine Reports: 1961 

Through 2006 (DOT/FAA/AM-07/1); 2007 Jan. 

Washington, DC: FAA Office of Aerospace Medicine; 2007:iv–xiv.

236. Sanders DC, Chaturvedi AK. An overview of aircraft fires, smoke toxicity, and survival -- Part I. In: 

Federal Air Surgeon’s Medical Bulletin. Oklahoma 

City, OK: FAA Civil Aeromedical Institute; 1994. 

p. 1 & 6.

237. Sanders DC, Chaturvedi AK, Endecott BR, Ritter 

RM, Vu N. Toxicity of carbon monoxide-hydrogen 

cyanide gas mixtures: Exposure concentration, 

time-to-incapacitation, carboxyhemoglobin, and 

blood cyanide parameters. Washington, DC: FAA 

Office of Aviation Medicine; 1994 Apr. Report No: 

DOT/FAA/AM-94/7.

238. Sanders DC, Chaturvedi AK, Hordinsky JR. 

Melatonin: Aeromedical, toxicopharmacological, and analytical aspects. J Anal Toxicol 1999; 

23(3):159–67.

239. Sanders DC, Crane CR, Endecott BR. Inhalation 

toxicology: V. Evaluation of relative toxicity to 

rats of thermal decomposition products from two 

aircraft seat fire-blocking materials. Washington, 

DC: FAA Office of Aviation Medicine; 1985 Nov. 

Report No: DOT/FAA-AM-86-1.

240. Sanders DC, Endecott BR. Inhalation toxicology: 

XI. The effect of elevated temperature on carbon 

monoxide toxicity. Washington, DC: FAA Office of Aviation Medicine; 1990 Dec. Report No: 

DOT/FAA/AM-90/16.
40

241. Sanders DC, Endecott BR. The effect of elevated 

temperature on carbon monoxide-induced incapacitation. J Fire Sci 1991; 9(4):296–310.

242. Sanders DC, Endecott BR. The effect of elevated 

temperature on carbon monoxide-induced incapacitation. In: Hartzell GE, ed. Advances in 

combustion toxicology. Lancaster, PA: Technomic 

Publishing Co., Inc.; 1992:343–57.

243. Sanders DC, Endecott BR, Chaturvedi AK. Inhalation toxicology: XII. Comparison of toxicity 

rankings of six polymers by lethality and by incapacitation in rats. Washington, DC: FAA Office 

of Aviation Medicine; 1991 Dec. Report No: 

DOT/FAA/AM-91/17.

244. Sanders DC, Endecott BR, Chaturvedi AK. Comparison of toxicity rankings of six aircraft cabin 

polymers by lethality and by incapacitation in rats. 

Aviat Space Environ Med 1992; 63(10):870–4.

245. Sanders DC, Endecott BR, Ritter RM, Chaturvedi

AK. Variations of time-to-incapacitation and 

carboxyhemoglobin values in rats exposed to two 

carbon monoxide concentrations. Washington, 

DC: FAA Office of Aviation Medicine; 1993 May. 

Report No: DOT/FAA/AM-93/7.

246. Sanderson JH, Sotheran MF, Stattersfield JP. A new 

method of carboxyhaemoglobin determination. Br 

J Ind Med 1978; 35(1):67–72.

247. Schwerd W, Schulz E. Carboxyhaemoglobin and 

methaemoglobin findings in burnt bodies. Forensic 

Sci Int 1978; 12(3):233–5.

248. Sen A, Akin A, Canfield DV, Chaturvedi AK. 

Medical histories of 61 aviation accident pilots 

with postmortem SSRI antidepressant residues. 

Aviat Space Environ Med 2007; 78(11):1055–9.

249. Sen A, Akin A, Canfield DV, Chaturvedi AK. Selective serotonin reuptake inhibitors: Medical history 

of fatally injured aviation accident pilots. Washington, DC: FAA Office of Aerospace Medicine; 2007 

Jul. Report No: DOT/FAA/AM-07/19.

250. Sen A, Akin A, Craft KJ, Canfield DV, Chaturvedi

AK. First-generation H1 antihistamines found in 

pilot fatalities of civil aviation accidents, 1990-2005. 

Aviat Space Environ Med 2007; 78(5):514–22.

251. Sen A, Akin A, Craft KJ, Canfield DV, Chaturvedi

AK. First-generation H1

 antihistamines found in 

pilot fatalities of civil aviation accidents, 1990–2005. 

Washington, DC: FAA Office of Aerospace Medicine; 

2007 May. Report No: DOT/FAA/AM-07/12.

252. Seto Y. Stability and spontaneous production of 

blood cyanide during heating. J Forensic Sci 1996; 

41(3):465–8.

253. Silverman SH, Purdue GF, Hunt JL, Bost RO. 

Cyanide toxicity in burned patients. J Trauma 1988; 

28(2):171–6.

254. Smith PW. Toxic hazards in aerial application. Oklahoma City, OK: FAA Civil Aeromedical Research 

Institute; 1962 Apr. Report No: FAA-AM-62-8.

255. Smith PW, Lacefield DJ, Crane CR. Toxicological 

findings in aircraft accident investigation. Aerosp 

Med 1970; 41(7):760–2.

256. Smith PW, Robinson CP, Zelenski JD, Endecott 

BR. The role of monamine oxidase inhibition in 

the acute toxicity of chlordimeform. Washington, 

DC: FAA Office of Aviation Medicine; 1977 Aug. 

Report No: FAA-AM-77-19.

257. Smith PW, Stavinoha WB, Ryan LC. Cholinesterase 

inhibition in relation to fitness to fly. Aerosp Med 

1968; 39(7):754–8.

258. Smith RP. Toxic responses of the blood. In: Klaassen 

CD, Amdur MO, Doull J, eds. Casarett & Doull’s 

toxicology: The basic science of poisons. 5th ed. 

New York, NY: McGraw-Hill; 1996:335−54.

259. Smyth KC, Norton TS, Miller JH, Smooke MD. 

Comparison of experimental and computed species 

concentration and temperature profiles in laminar, 

two-dimensional CH4/air diffusion flames. In: 

Smith SB, editor. Abstracts: annual conference on 

fire research (NISTIR 4924); October 13–15, 1992; 

Rockville, MD: U.S. Department of Commerce, 

Technology Administration, National Institute 

of Standards and Technology, Building and Fire 

Research Laboratory; 1992;57–8.

260. SOFT/AAFS. The Society of Forensic Toxicologists, Inc. (SOFT)/American Academy of Forensic 

Sciences (AAFS) forensic toxicology laboratory 

guidelines, 2006 version; Retrieved 09 April 2008 

from www.soft-tox.org/docs/Guidelines%202006

%20Final.pdf.

261. Solomon KR, Thompson DG. Ecological risk assessment for aquatic organisms from over-water uses 

of glyphosate. J Toxicol Environ Health B Crit Rev 

2003; 6(3):289–324.

262. Soper JW, Chaturvedi AK, Canfield DV. Prevalence 

of chlorpheniramine in aviation accident pilot 

fatalities, 1991-1996. Aviat Space Environ Med 

2000; 71(12):1206–9.
41

263. Speitel LC. Fractional effective dose model for 

post-crash aircraft survivability. Toxicology 1996; 

115(1–3):167–77.

264. Strahle WC. An introduction to combustion. 

Amsterdam, Netherlands: Gordon and Breach 

Publishers; 1993:41–52.

265. Strøm-Tejsen P, Weschler CJ, Wargocki P, Myśków 

D, Zarzycka J. The influence of ozone on selfevaluation of symptoms in a simulated aircraft 

cabin. J Expo Sci Environ Epidemiol 2008; 

18(3):272–81. 

266. Strøm-Tejsen P, Wyon DP, Lagercrantz L, Fang 

L. Passenger evaluation of the optimum balance 

between fresh air supply and humidity from 7-h 

exposures in a simulated aircraft cabin. Indoor Air 

2007; 17(2):92–108.

267. Sylvester DM, Holmes RK, Sander C, Way JL. 

Interference of thiosulfate with potentiometric 

analysis of cyanide in blood and its elimination. 

Toxicol Appl Pharmacol 1982; 65(1):116–21.

268. Symington IS, Anderson RA, Thomson I, Oliver 

JS, Harland WA, Kerr JW. Cyanide exposure in 

fires. Lancet 1978; 2(8080):91–2.

269. The Encyclopedia Americana. Aviation. In: The 

Encyclopedia Americana International edition. 

Danbury, CT: Grolier Incorporated; 1989. p. 

859.

270. Thibeault C. Cabin air quality. Aerospace Medical Association. Aviat Space Environ Med 1997; 

68(1):80–2.

271. Thibeault C. Airliner cabin air quality. Occup Med 

2002; 17(2):279–92.

272. Tietz NW, Fiereck EA. The spectrophotometric 

measurement of carboxyhemoglobin. Ann Clin 

Lab Sci 1973; 3(1):36–42.

273. Tracqui A, Raul JS, Geraut A, Berthelon L, Ludes 

B. Determination of blood cyanide by HPLC-MS. 

J Anal Toxicol 2002; 26(3):144-8.

274. Troup CM, Ballantyne B. Analysis of cyanide in 

biological fluids and tissues. In: Ballantyne B, Marrs 

TC, eds. Clinical and experimental toxicology of 

cyanides. Bristol, UK: Wright; 1987:22–40.

275. TSB. In-flight fire leading to collision with water: 

Swissair Transport Limited McDonnell Douglas 

MD-11 HB-IWF, Peggy’s Cove, Nova Scotia 5 

nm SW, 2 September 1998. Gatineau, Quebec, 

Canada: Transportation Safety Board of Canada 

(TSB) Report No: A98H0003.

276. U.S. National Aeronautics and Space Administration. Apollo 1: The fire 27 January 1967; Retrieved 

14 February 2008 from www.history.nasa.gov/SP4029/Apollo_01a_Summary.htm.

277. U.S. National Aeronautics and Space Administration. STS-95 (92); Retrieved 13 June 2008 from 

science.ksc.nasa.gov/shuttle/missions/sts-95/mission-sts-95.html.

278. U.S. National Toxicology Program. NTP toxicology 

and carcinogenesis studies of ethylbenzene (CAS 

No. 100-41-4) in F344/N rats and B6C3F1 mice 

(inhalation studies). Natl Toxicol Program Tech 

Rep Ser 1999; 466:1–231.

279. Uges DRA. Hospital toxicology. In: Moffat AC, 

Osselton MD, Widdop B, Galichet LY, eds. Clarke’s 

analysis of drugs and poisons in pharmaceuticals, 

body fluids and postmortem material. 3rd ed. 

London, UK: Pharmaceutical Press; 2004:3–36.

280. Uva Ade S. [Aircraft cabin air quality: exposure to 

ozone]. Acta Med Port 2002; 15(2):143–51.

281. van Netten C. Multi-elemental analysis of jet engine 

lubricating oils and hydraulic fluids and their implication in aircraft air quality incidents. Sci Total 

Environ 1999; 229(1–2):125–9.

282. van Netten C, Leung V. Comparison of the constituents of two jet engine lubricating oils and their 

volatile pyrolytic degradation products. Appl Occup 

Environ Hyg 2000; 15(3):277–83.

283. van Netten C, Leung V. Hydraulic fluids and jet 

engine oil: Pyrolysis and aircraft air quality. Arch 

Environ Health 2001; 56(2):181–6.

284. Vesey CJ, Wilson J. Red cell cyanide. J Pharm 

Pharmacol 1978; 30(1):20–6.

285. Vieillefond H, Fourn P, Auffret R. Characteristics in 

the atmosphere of long-range transport aircraft cab-

ins. Aviat Space Environ Med 1977; 48(6):503–7.

286. Von Burg R. Carbon monoxide. J Appl Toxicol 

1999; 19(5):379–86.
42

287. Vu NT, Chaturvedi AK, Canfield DV, Soper JW, 

Kupfer DM, Roe BA. DNA-based detection of 

ethanol-producing microorganisms in postmortem 

blood and tissues by polymerase chain reaction. 

Washington, DC: FAA Office of Aviation Medicine; 

2000 May. Report No: DOT/FAA/AM-00/16.

288. Way JL. Cyanide intoxication and its mechanism 

of antagonism. Annu Rev Pharmacol Toxicol 1984; 

24:451–81.

289. Welch B, Navias R. Small fire extinguished on 

Mir. Retrieved 14 February 2008 from www.nasa.

gov/centers/johnson/news/releases/1996_1998/97-

30.html.

290. Wetherell HP. The occurrence of cyanide in the blood 

of fire victims. J Forensic Sci 1966; 11:167–73.

291. White VL, Chaturvedi AK, Canfield DV, Garber 

M. Association of postmortem blood hemoglobin 

A1c levels with diabetic conditions in aviation accidents pilot fatalities. Washington, DC: FAA Office of Aerospace Medicine; 2001 Jul. Report No: 

DOT/FAA/AM-01/12.

292. Wick RL, Jr., Irvine LA. The microbiological composition of airliner cabin air. Aviat Space Environ 

Med 1995; 66(3):220–4.

293. Widdop B. Analysis of carbon monoxide. Ann Clin 

Biochem 2002; 39(Pt 4):378–91.

294. Wieslander G, Lindgren T, Norback D, Venge P. 

Changes in the ocular and nasal signs and symptoms of aircrews in relation to the ban on smoking 

on intercontinental flights. Scand J Work Environ 

Health 2000; 26(6):514–22.

295. Williams LA. Toxicology. In: Frankel S, Reitman S, 

Sonnenwirth AC, eds. Gradwohl’s clinical laboratory methods and diagnosis. 7th ed. St. Louis, MO: 

C.V. Mosby Company; 1970:303–5.

296. Williams LA. Carbon monoxide: Type A procedure. In: Sunshine I, ed. Methodology for analytical toxicology. Boca Raton, FL: CRC Press, Inc.; 

1975:64–6.

297. Williams LA, Linn RA, Zak B. Ultraviolet absorptiometry of palladium for determination of carbon 

monoxide hemoglobin. Am J Clin Pathol 1960; 

34:334–7.

298. Winek CL, Prex DM. A comparative study of analytical methods to determine postmortem changes 

in carbon monoxide concentration. Forensic Sci Int 

1981; 18(2):181–7.

299. Wood W, Gabica J, Brown HW, Watson M, Benson 

WW. Implication of organophosphate pesticide 

poisoning in the plane crash of a duster pilot. Aerosp 

Med 1971; 42(10):1111–3.

300. Wyss R, Stossel U, Muff S. [Air travel--a disease 

risk? ]. Ther Umsch 2001; 58(6):399–403.

301. Yajima D, Motani H, Kamei K, Sato Y, Hayakawa 

M, Iwase H. Ethanol production by Candida albicans in postmortem human blood samples: Effects 

of blood glucose level and dilution. Forensic Sci Int 

2006; 164(2–3):116–21.

302. Zamecnik J, Tam J. Cyanide in blood by gas chromatography with NP detector and acetonitrile as 

internal standard. Application on air accident fire 

victims. J Anal Toxicol 1987; 11(1):47–8.

FURTHER READING

Brunton LL, Lazo JS, Parker KL, Eds, Goodman & 

Gilman’s the pharmacological basis of therapeutics, 11th 

ed; McGraw-Hill, New York, NY; 2006.

Davis JR, Johnson R, Stepanek J, Fogarty JA, Eds, 

Fundamentals of Aerospace Medicine, 4th ed; Lippincott 

Williams & Wilkins, Philadelphia, PA; 2008.

Klaassen CD, Editor, Casarett & Doull’s toxicology: 

The basic science of poisons, 7th ed; McGraw-Hill, New 

York, NY; 2008.

Rainford DJ, Gradwell DP, Eds, Ernsting’s aviation 

medicine, 4th ed; Hodder Arnold, London, UK; 2006.