TOXICOLOGICAL PROFILE FOR

N-NITROSODIMETHYLAMINE

Agency for Toxic Substances and Disease Registry (ATSDR)

U.S. Public Health Service

In collaboration with

U.S. Environmental Protection Agency (EPA)

December 1989
ii

DISCLAIMER

Mention of company name or product does not constitute endorsement by the

Agency for Toxic Substances and Disease Registry.
iii

FOREWORD

The Superfund Amendments and Reauthorization Act of 1986 (Public

Law 99-499) extended and amended the Comprehensive Environmental Response,

Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public

law (also known as SARA) directed the Agency for Toxic Substances and Disease

Registry (ATSDR) to prepare toxicological profiles for hazardous substances

which are most commonly found at facilities on the CERCLA National Priorities

List and which pose the most significant potential threat to human health, as

determined by ATSDR and the Environmental Protection Agency (EPA). The lists

of the most significant hazardous substances were published in the Federal

Register on April 17, 1987, and on October 20, 1988.

Section 110 (3) of SARA directs the Administrator of ATSDR to prepare a

toxicological profile for each substance on the list. Each profile must

include the following content:

(A) An examination, summary and interpretation of available

toxicological information and epidemiological evaluations on the

hazardous substance in order to ascertain the levels of significant

human exposure for the substance and the associated acute, subacute,

and chronic health effects,

(B) A determination of whether adequate information on the health

effects of each substance is available or in the process of

development to determine levels of exposure which present a

significant risk to human health of acute, subacute, or chronic

health effects, and

(C) Where appropriate, an identification of toxicological testing

needed to identify the types or levels of exposure that may present

significant risk of adverse health effects in humans.

This toxicological profile is prepared in accordance with guidelines

developed by ATSDR and EPA. The original guidelines were published in the

Federal Register on April 17, 1987. Each profile will be revised and

republished as necessary, but no less often than every 3 years, as required

by SARA.

The ATSDR toxicological profile is intended to characterize succinctly

the toxicological and health effects information for the hazardous substance

being described. Each profile identifies and reviews the key literature that









1

1. PUBLIC HEALTH STATEMENT

1.1 WHAT IS N-NITROSODIMETHYhYMINE?

N-Nitrosodimethylamine is commonly known as NDMA. It is a yellow

liquid which has no distinct odor. It is produced in the U.S. only for use

as a research chemical. NDMA was used to make rocket fuel, but this use

was stopped after unusually high levels of this compound were found in air,

water, and soil samples collected near a rocket fuel manufacturing plant.

NDMA is, however, unintentionally formed during various manufacturing

processes at many industrial sites and in air, water and soil from reactions

involving other chemicals called alkylamines. Alkylamines are both natural

and man-made compounds which are found widely distributed throughout the

environment.

NDMA does not persist in the environment. When NDMA is released into

the atmosphere, it breaks down in sunlight in a matter of minutes. When

released to soil surfaces, NDMA may evaporate into air, break down upon

exposure to sunlight, or sink into deeper soil. NDMA should break down

within a few months in deep soil. When NDMA is released into water, it may

break down upon exposure to sunlight or break down by natural biological

processes. The rate of breakdown in water is not known. More information

can be found in Chapters 3, 4 and 5.

1.2 HOW MIGHT I BE EXPOSED TO N-NITROSODIMETHYLAMINE?

Information suggests that the general population may be exposed to NDMA

from a wide variety of sources, including environmental, consumer, and

occupational sources. At this time, NDMA has been found in at least 1 out

of 1177 hazardous waste sites on the National Priorities List (NPL) in the

United States. Under certain conditions, NDMA may be found in outdoor air,

surface waters (rivers and lakes, for example), and soil. The primary

sources of human exposure to NDMA are tobacco smoke, chewing tobacco, diet

[cured meats (particularly bacon), beer, fish, cheese, and other food

items], toiletry and cosmetic products (for example, shampoos and

cleansers), interior air of cars, and various other household goods, such as

detergents and pesticides. In addition, NDMA can form in the stomach during

digestion of alkylamine-containing foods. Alkylamines are naturally

occurring compounds which are found in some drugs and in a variety of foods.

Infants may be exposed to NDMA from the use of rubber baby bottle nipples

and pacifiers which may contain very small amounts of NDMA, from ingestion

of contaminated infant formulas, and from breast milk of some nursing

mothers. Very low levels of NDMA have been found in some samples of human

breast milk. Occupational exposure may happen in a large number of places

including industries such as tanneries, pesticide manufacturing plants,

rubber and tire manufacturing plants, alkylamine manufacture/use industries,

fish processing industries, foundries, and dye manufacturing plants.

Researchers making or handling NDMA may also be exposed to this compound if

It passes through the rubber gloves they wear during laboratory work. NDMA
2

1. PUBLIC HEALTH STATEMENT

has been found in groundwater samples, in amounts of 10 parts NDMA per

billion parts of water, at one or more hazardous waste sites on the

National Priorities List (NPL). No information is available about

contamination of soil, drinking water, irrigation water, sewers, storm

drains, or the human food chain with NDMA near NPL sites. For more

information, refer to Chapter 5.

1.3 HOW CAN N-NITROSODIMETHYIAMINE ENTER AND LEAVE MY BODY?

NDMA can enter the body when a person breathes air that contains NDMA

or when a person eats food or drinks water contaminated with NDMA. NDMA can

also enter the body through the skin after contact with rubber articles that

contain NDMA. Experiments in animals have shown that after being given by

mouth, NDMA enters the bloodstream and goes to many organs of the body in a

matter of minutes. In the liver, NDMA is broken down into other substances,

most of which leave the body within 24 hours in air exhaled from the lungs

and in urine, along with the NDMA that is not broken down. Little is known

about what happens to NDMA that enters the body through the skin or through

contaminated air. Although vapors of NDMA are broken down within minutes

after exposure to sunlight, if NDMA is spilled at a waste site and

evaporates, a person nearby can be exposed to NDMA before it disappears from

the air. The most important and probably the most harmful way of coming

into contact with NDMA seems to be by eating contaminated food or drinking

contaminated water. Further information on how NDMA can enter and leave the

body can be found in Chapter 2.

1.4 HOW CAN N-NITROSODIMETHYUMINE AFFECT MY HEALTH?

NDMA is very harmful to the liver of animals and humans. People who

were intentionally poisoned on one or several occasions with unknown levels

of NDMA in beverage or food died of severe liver damage accompanied by

internal bleeding. Animals that ate food, drank water, or breathed air

containing high levels of NDMA over a period of days or several weeks also

developed serious, non-cancerous, liver disease. When rats, mice, hamsters,

and other animals ate food, drank water, or breathed air containing lower

levels of NDMA for periods more than several weeks, liver cancer and lung

cancer as well non-cancerous liver damage occurred. The high level shortterm and low level long-term exposures that caused non-cancerous liver

damage and/or cancer in animals also usually resulted in internal bleeding

and death. Although there are no reports of NDMA causing cancer in humans,

it is reasonable to expect that exposure to NDMA by eating, drinking, or

breathing could cause cancer in humans. Mice that were fed NDMA during

pregnancy had offspring that were born dead or died shortly after birth.

However, it is not known whether NDMA could cause the death of human babies

whose mothers are exposed during pregnancy. It should be realized that

exposure to NDMA does not mean that any effect on health will definitely

occur.
3

1. PUBLIC HEALTH STATEMENT

1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO

NITROSODIMETHWAMINE?

The presence of NDMA can be detected in blood and urine by a test, but

this test is not usually available and has not been used as a test for

human exposure or to predict possible health effects.

1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?

The amounts of N-nitrosodimethylamine in air, drinking water, and food

that cause known health effects other than cancer in humans and animals are

summarized in Tables l-l, l-2, l-3, and 1-4. These amounts are expressed as

parts of NDMA per million parts of air, water, or food (ppm). As seen in

Tables l-1 and l-3, the amounts of NDMA in air, water, or food that result

in health effects in humans are unknown. As seen in Table 1-2, short-term

exposure of animals to air containing NDMA produces liver damage and death.

Toxic effects of long-term exposures of animals to air containing NDMA are

unknown. As seen in Table l-4, short-term or long-term exposure of animals

to water or food containing NDMA is also associated with serious effects,

such as liver disease and death. More information on levels of NDMA that

cause harmful effects in animals is presented in Chapter 2.

1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN

HEALTH?

The Federal government has issued guidelines and rules to protect human

health from exposure to NDMA in water and in food. The U.S. Environmental

Protection Agency (EPA) has set limits on the amounts of NDMA in water such

as lakes and streams. The EPA controls the release of NDMA. Releases or

spills of one pound or more of NDMA must be reported to the National

Response Center. The Food and Drug Administration (FDA) has set a limit of

10 parts of NDMA per billion parts of barley malt (ppb). Further

information on Federal and state regulations can be found in Chapter 7.

1.8 WHERE CAN I GET MORE INFORMATION?

If you have more questions or concerns, please contact your State

Health or Environmental Department or:

Agency for Toxic Substances and Disease Registry

Division of Toxicology

1600 Clifton Road, E-29

Atlanta, Georgia 30333





9

2. HEALTH EFFECTS

2.1 INTRODUCTION

This chapter contains descriptions and evaluations of studies and

interpretation of data on the health effects associated with exposure to

NDMA. Its purpose is to present levels of significant exposure for NDMA

based on toxicological studies, epidemiological investigations, and

environmental exposure data. This information is presented to provide

public health officials, physicians, toxicologists, and other interested

individuals and groups with (1) an overall perspective of the toxicology of

NDMA and (2) a depiction of significant exposure levels associated with

various adverse health effects.

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

To help public health professionals address the needs of persons

living or working near hazardous waste sites, the data in this section are

organized first by route of exposure -- inhalation, oral, and dermal -- and

then by health effect -- death, systemic, immunological, neurological,

developmental, reproductive, genotoxic, and carcinogenic effects. These

data are discussed in terms of three exposure periods -- acute,

intermediate, and chronic.

Levels of significant exposure for each exposure route and duration

(for which data exist) are presented in tables and illustrated in figures.

The points in the figures showing no-observed-adverse-effect levels (NOAELS)

or lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses

(levels of exposure) used in the studies. LOAELs have been classified into

"less serious" or "serious" effects. These distinctions are intended to

help the users of the document identify the levels of exposure at which

adverse health effects start to appear, determine whether or not the

intensity of the effects varies with dose and/or duration, and place into

perspective the possible significance of these effects to human health.

The significance of the exposure levels shown on the tables and graphs

may differ depending on the user's perspective. For example, physicians

concerned with the interpretation of clinical findings in exposed persons or

with the identification of persons with the potential to develop such

disease may be interested in levels of exposure associated with "serious"

effects. Public health officials and project managers concerned with

response actions at Superfund sites may want information on levels of

exposure associated with more subtle effects in humans or animals (LOAEL) or

exposure levels below which no adverse effects (NOAEL) have been observed.

Estimates of levels posing minimal risk to humans (minimal risk levels,

MRLs) are of interest to health professionals and citizens alike.

For certain chemicals, levels of exposure associated with carcinogenic

effects may be indicated in the figures. These levels reflect the actual
10

2. HEALTH EFFECTS

doses associated with the tumor incidences reported in the studies cited.

Because cancer effects could occur at lower exposure levels, the figures

also show estimated excess risks, ranging from a risk of one in 10,000 to

one in 10,000,000 (10-4 to 10-7), as developed by EPA.

Estimates of exposure levels posing minimal risk to humans (MRLs) have

been made, where data were believed reliable, for the most sensitive

noncancer end point for each exposure duration. MRLs include adjustments to

reflect human variability and, where appropriate, the uncertainty of

extrapolating from laboratory animal data to humans. Although methods have

been established to derive these levels (Barnes et al. 1987; EPA 1980a),

uncertainties are associated with the techniques.

2.2.1 Inhalation Exposure

2.2.1.1 Death

At least two human deaths following inhalation of NDMA have been

reported in the literature. One was a male chemist who was involved in the

production of NDMA and was exposed to an unknown level of fumes for about

two weeks, and subsequently to an unknown level of fumes during cleanup of a

spilled flask (Freund 1937). The subject became ill 6 days later, showed

abdominal distention, large amounts of yellow ascitic fluid, a tender and

enlarged liver and enlarged spleen, and died 6 weeks after the last

exposure. The other death was that of a male worker who was exposed to

unknown concentrations of NDMA in an automobile factory. Autopsy of this

subject showed a cirrhotic liver with areas of regeneration (Hamilton and

Hardy 1974).

The lethality of inhaled NDMA has been evaluated in several acute

duration studies with animals. Four-hour single exposure LC50 values of 78

ppm (95% confidence limits of 68 and 90 ppm) and 57 ppm (95% confidence

limits of 51 and 64 ppm) were determined for rats and mice, respectively

(Jacobson et al. 1955). The observation time in these assays was 14 days.

The cause of death was not specified but liver damage and hemorrhage in

various abdominal tissues were predominant pathologic findings. Druckrey

(1967) reported that the "LD50" for rats exposed to NDMA by inhalation for

one hour is 37 mg/kg. The air concentration corresponding to this dose is

not reported but a value of 925 ppm can be calculated from information

provided in the report; confidence in this value is low, however, because

this information is ambiguously reported. Two of three dogs that were

exposed to 16 ppm NDMA for 4 hours died or were moribund by the second day

(Jacobson et al. 1955). All dogs that were similarly exposed to 43-144 ppm

died or were moribund after 1-3 days. The 57 ppm mouse and 78 ppm rat LC50

values are presented in the acute duration category in Table 2-1 and Figure

2-1. The Druckrey (1967) rat value is not included in Table 2-1 and Figure

2-1 due to uncertainty regarding its validity. The 16 ppm concentration

represents a LOAEL for lethality in dogs due to acute duration inhalation


13

2. HEALTH EFFECTS

exposure (Table 2-l and Figure 2-l). The concentration of 16 ppm in air

(Jacobson et al. 1955) is presented in Table l-2.

2.2.1.2 Systemic Effects

No studies were located regarding musculoskeletal or renal effects in

humans or animals following inhalation exposure to NDMA.

Respiratory Effects. Freund (1937) observed small hemorrhages in the

bronchi and trachea of a person who died from accidental exposure to vapors

of NDMA (Section 2.2.1.1).

No studies were located regarding respiratory effects in animals

following.inhalation exposure to NDMA.

Cardiovascular Effects. Subpericardial hemorrhage was observed in a

person who died from accidental exposure to vapors of NDMA (Freund 1937)

(Section 2.2.1.1).

No studies were located regarding cardiovascular effects in animals

following inhalation exposure to NDMA.

Gastrointestinal Effects. Gastrointestinal hemorrhage was observed in

a person who died from accidental exposure to vapors of NDMA (Freund 1937)

(Section 2.2.1.1).

No studies were located regarding gastrointestinal effects in animals

following inhalation exposure to NDMA.

Hematological Effects. No studies were located regarding hematological

effects in humans following inhalation exposure to NDMA.

Hematological determinations were performed in dogs that were exposed

to 16-144 ppm NDMA for 4 hours (Jacobson et al. 1955). Increased coagulation

time, increased prothrombin time, increased plasma cholinesterase levels and

leukopenia occurred following exposure to all concentrations. There was no

evidence of intravascular hemolysis. As indicated in Section 2.2.1.1, the

concentrations producing these effects were lethal. Pathologic examination

of the dogs showed bloody ascites and hemorrhage in the liver and other

abdominal tissues, Due to the clinical evidence of impaired blood

coagulation and the possibility that the hemorrhagic effects were related to

impaired coagulation, 16 ppm is a LOAEL for hematological effects due to

acute inhalation exposure (Table 2-l and Figure 2-l).

Hepatic Effects. Four cases of liver disease in humans resulting from

inhalation exposure to NDMA have been described in the literature. Two of

the subjects died; these cases are discussed in Section 2.2.1.1. Of the

subjects who did not die, one was a chemist who was exposed to unknown

concentrations of fumes and experienced exhaustion, headache, cramps in the
14

2. HEALTH EFFECTS

abdomen, soreness on the left side, nausea and vomiting for at least two

years (Freund, 1937). The second case was an automobile factory worker who

was exposed to unknown levels of NDMA and became violently ill with jaundice

and ascites (Hamilton and Hardy 1974).

Hepatotoxicity is a predominant effect of high concentrations of

inhaled NDMA in animals. Pathologic examination of dogs following exposure

to 16-144 ppm NDMA for 4 hours showed marked necrosis and varying degrees of

hemorrhage in the liver (Jacobson et al. 1955). Related effects at all

concentrations included increased bilirubin levels and increased

sulfobromophthalein retention. As indicated in Section 2.2.1.1, the

concentrations producing these effects were lethal. Jacobson et al. (1955)

also indicated that necrosis and hemorrhage occurred in the liver of rats

and mice that were exposed to lethal concentrations of NDMA for 4 hours; as

indicated in Section 2.2.1.1, LC50 values for the rats and mice are 78 and

57 ppm, respectively. The 16 ppm, 57 and 78 ppm concentrations represent

LOAELs for hepatic effects due to acute inhalation exposure and are

presented in Table 2-l and Figure 2-l. The concentration of 16 ppm in air

(Jacobson et al. 1955) is presented in Table l-2.

Dennal/Ocular Effects. No studies were located regarding dermal or

ocular effects in humans following inhalation exposure to NDMA.

Limited information is available regarding dermal or ocular effects of

inhaled NDMA. Doolittle et al. (1984) reported that the only toxic signs

observed in rats exposed to 500 or 1000 ppm for 4 hours were reddened eyes

and piloerection. The only additional information reported in this study

pertained to genotoxic effects. Although high concentrations of NDMA vapor

are likely to be irritating, the significance of the reddened eyes and

piloerection cannot be determined because it is not specified if the effects

occurred at both concentrations and prevalence is not indicated. As

indicated in Section 2.2.1.1, acute exposure to much lower concentrations of

NDMA was lethal for rats, mice and dogs. The lack of mortality in rats at

the higher concentrations in the Doolittle et al. (1984) study may be

attributable to the fact that the animals were killed immediately following

exposure and consequently not observed for subsequent death.

No studies were located regarding the following effects in humans or

animals following inhalation exposure to NDMA:

2.2.1.3 Immunological Effects

2.2.1.4 Neurological Effects

2.2.1.5 Developmental Effects

2.2.1.6 Reproductive Effects
15

2. HEALTH EFFECTS

2.2.1.7 Genotoxic Effects

No studies were located regarding genotoxic effects in humans following

inhalation exposure to NDMA.

Rats exposed to 500 or 1000 ppm of NDMA in the air for 4 hours showed

chemically induced DNA repair in epithelial cells in the nasal turbinates

and trachea. DNA repair was also evident in hepatocytes, indicating that the

substance entered the general circulation. No DNA repair was seen in the

pachytene spermatocytes, indicating that NDMA either did not reach the

testes in high enough concentrations, or that the testes could not

metabolically activate the compound (Doolittle et al. 1984). It should be

noted that the exposures in this study are likely to have been lethal if the

rats had.been observed following treatment; as indicated in Section 2.2.1.1,

4-hour exposure to much lower concentrations of NDMA was lethal for rats,

mice and dogs in other studies.

2.2.1.8 Cancer

No studies were located regarding carcinogenic effects in humans

following inhalation exposure to NDMA.

The carcinogenicity of inhaled NDMA has been evaluated in two studies.

Twice weekly 30-minute exposures to 50 or 100 ppm NDMA vapor for life

produced malignant nasal cavity tumors in rats (Druckrey et al. 1967). The

incidence of tumors was 67% in each group, and the time to induce tumors in

50% of the rats was 400 days. Group sizes were small (12 and 6 animals at 50

and 100 ppm, respectively), control data were not reported, and additional

information regarding longevity was not provided. The 50 ppm concentration

is included in Table 2-l and Figure 2-l as an effect level for cancer

(cancer effect level, CEL) in rats due to intermittent inhalation exposure

of chronic duration.

Rats and mice that were continuously exposed to 0.07 ppm NDMA for 25

and 17 months, respectively, developed significantly increased incidences of

lung, liver and kidney tumors (Moiseev and Benemanski 1975). Tumor types

included various adenomas, carcinomas, and sarcomas in the lung, liver and

kidneys, and hemangiomas in the liver, but the types were not tabulated

according to species or concentration. Induction of nasal tumors was not

reported. Exposure to 0.002 ppm NDMA according to the same schedule did not

produce significantly increased incidences of tumors in either species.

Since the tumors associated with exposure to 0.07 ppm NDMA are consistent

with those produced by NDMA in oral and injection studies and the study is

reported adequately otherwise, 0.07 ppm is considered to be a CEL for rats

and mice due to continuous inhalation exposure of chronic duration (Table

2-1, Figure 2-l).

EPA has adopted the oral carcinogenicity slope factor (BH) of 51

(mg/kg/day) -1 ( see Section 2.2.2.8) as the slope factor for inhalation (EPA
16

2. HEALTH EFFECTS

1988a). The oral slope factor was converted to a unit risk for inhalation of

1.4 x 10-2 (•g/m3

)-1, which is equivalent to 42.4 (ppm)-1. Using this unit

risk, the concentrations associated with upper bound lifetime cancer risk

levels of 10-4 to 10-7 are calculated to be 2.36 x 10-6 to 2.36 x 10-9 

ppm,

respectively. The cancer risk levels are plotted in Figure 2-l.

2.2.2 Oral Exposure

2.2.2.1 Death

At least three human deaths following oral exposure to NDMA have been

reported in the literature. One of the fatalities was a woman who was

apparently poisoned over a two-year period by her husband (Fussgaenger and

Ditschuneit 1980, Pedal et al. 1982). It was estimated by the authors that

she received at least 4 doses as high as 250-300 mg each, for a total dose

of less than 1.5 gram; the mean daily dose was estimated to be 50 •g/kg.

Both clinical and autopsy findings indicated that she died of hepatic

failure. Two other people (an adult male and a l-year-old boy) died within

days after consuming lemonade tainted with unknown quantities of NDMA

(Kimbrough 1982, Cooper and Kimbrough 1980). Based on animal studies, the

authors estimated that the adult might have received about 1.3 gm, and the

boy might have received about 300 mg. In both cases, clinical and autopsy

findings primarily showed liver failure and cerebral hemorrhage.

Single dose lethality studies have been conducted in which NDMA was

administered to rats and cats by gavage. Druckrey et al. (1967) determined a

LD50 of 40 mg/kg for rats. This value was determined using an unspecified

graphic technique, and confidence limits and specific mortality data were

not reported. All of 12 rats that were treated with 40 mg/kg in a skin

grafting (immunology) experiment died by day 21, but the stress of skin

graft rejection may have contributed to mortality (Waynforth and Magee

1974). Jenkins et al. (1985) reported that single 25 mg doses of NDMA

resulted in 100% mortality in an unspecified number of rats, but it is

unclear if this is dose per kg body weight or dose per total body weight.

Single doses of 15 and 20 mg/kg were not lethal for nonpregnant rats but 23

mg/kg was estimated to be the LD50 for pregnant rats (Nishie 1983). The LD50

for the pregnant rats was extrapolated using mortality of 18-day pregnant

rats given single oral doses of 15 or 20 mg NDMA/kg. A dose of 10 mg/kg did

not produce deaths in rats within 48 hours (Sumi and Miyakawa 1983). Two of

6 cats died when treated with 50 mg NDMA/kg (Maduagwu and Basir 1980). The

NOAEL and appropriate LOAEL values for lethality from these single dose

studies are included in the acute duration category in Table 2-2 and Figure

2-2. The 40 mg/kg and 23 mg/kg rat LD5Os are also presented in Table 2-2 and

Figure 2-2.

Rats, guinea pigs, cats and monkeys that were treated with NDMA by

gavage at a dose of 5 mg/kg/day for 11 days experienced 30-40% mortality;











28

2. HEALTH EFFECTS

mean survival times were 5-11 days (Maduagwu and Bassir 1980). Rats treated

by gavage daily with 8 mg/kg NDMA for 6 days experienced 10% mortality

within one month (McGiven and Ireton 1972). Administration of NDMA in the

drinking water at a daily dose of 9.5 mg/kg for one week resulted in

decreased survival in mice (Terracini et al. 1966). Administration of a

daily dose of 4 mg/kg/day in the drinking water of hamsters for 1, 2, 4, 7

or 14 days did not result in mortality (Ungar 1984). The hamster NOAEL value

and all LOAEL values for lethality from these repeated exposure studies are

recorded in Table 2-2 and plotted in Figure 2-2. The mouse dose of 9.5

mg/kg/day was calculated from the administered concentration of 50 ppm in

water (Terracini et al. 1966); this concentration is presented in Table l-4

for short-term exposure.

Numerous oral studies in which NDMA was administered for intermediate

durations (15-365 days) have been conducted. Deaths resulting from

intermediate duration exposure to NDMA were usually attributed to liver

toxicity or carcinogenicity. Representative lethal and nonlethal

intermediate duration exposures in various species are presented below.

In rats, decreased survival resulted when 0.32 mg NDMA/kg was given in

the drinking water for 5 days/week for 30 weeks (Lijinsky and Reuber 1984),

and when 6 mg/kg was administered by gavage for 2 days/week for 30 weeks

(Lijinsky et al. 1987). Control groups were not included in the latter study

but there was 100% mortality by 40 weeks after cessation of treatment.

Barnes and Magee (1954) administered NDMA in the diet to small numbers of

rats (6/group); 2.5 mg/kg/day produced no deaths, 5 mg/kg/day produced 100%

mortality after 62-93 days, and 10 mg/kg/day produced 100% mortality after

34-37 days. Rats treated with 3.9 mg/kg/day in the diet for 40 weeks also

had high mortality (Magee and Barnes 1956). Daily exposure to 1 mg/kg/day by

gavage for 30 days had no effect on survival of rats (Maduagwu and Bassir

1980). Jenkins et al. (1985) observed mortality in rats that received 2.5 mg

doses of NDMA by gavage for 4 days/week for 9 weeks, but it is unclear if

this is dose per kg body weight or dose per total body weight. The NOAEL

values and all reliable LOAEL values for lethality in rats from these

intermediate duration studies are recorded in Table 2-2 and plotted in

Figure 2-2. The rat dose of 5 mg/kg/day was calculated from the administered

concentration of 100 ppm in diet (Barnes and Magee 1954); this concentration

is presented in Table l-4 for long-term exposure. The rat dose of 0.32

mg/kg/day was calculated from the administered concentration of 5.5 ppm in

water (Lijinsky and Reuber 1984); this concentration is also presented in

Table l-4 for long-term exposure.

In intermediate duration studies with mice, decreased survival resulted

from treatment with doses of 1.8 mg/kg/day via drinking water for 49 days

(Clapp and Toya 1970), 1.9 mg/kg/day via drinking water for 13 weeks (Den

Engelse et al. 1974), 1.19 mg/kg/day via drinking water for 38 weeks

(Terracini et al. 1966) and 5.26 mg/kg/day via diet for 5 months (Takayama

and Oota 1965). Mice that received 0.4 mg/kg/day in drinking water for 224

days did not experience significantly decreased survival (Clapp and Toya
29

2. HEALTH EFFECTS

1970). The NOAEL value and all LOAEL values for lethality in mice from these

intermediate duration studies are recorded in Table 2-2 and plotted in

Figure 2-2.

Survival data for intermediate oral exposure to NDMA are available for

species other than rat and mouse. Daily gavage exposure to 1 mg NDMA/kg for

30 days caused decreased survival in cats but not guinea pigs or monkeys

(Maduagwu and Bassir 1980). In hamsters, daily administration of 4 mg/kg/day

in the drinking water for 8, 12, or 16 weeks resulted in occasional

moribundity (Ungar 1986), while no lethality resulted from daily

administration of the same dose for 28 days (Ungar 1984); this dose is a

NOAEL or LOAEL for lethality depending on duration of exposure. Once weekly

gavage treatment with a dose of 10.7 mg/kg for 4 weeks or 5.4 mg/kg for 20

weeks was lethal for hamsters (Lijinsky et al. 1987). Mink that were given

doses of 0.32 or 0.63 mg/kg/day in the diet died after 23-34 days of

treatment (Carter et al. 1969), but low numbers of animals were tested

(three per dose). Mink fed a contaminated diet that provided approximately

0.18 mg NDMA/kg/day died (Martin0 et al. 1988), but there is uncertainty

about the dietary concentration of NDMA used to calculate the dose. The mink

that were examined in this study were from a commercial breeding colony that

died during a 2 month period; durations of exposure were not specified. The

NOAEL values and all reliable LOAEL values for lethality in these

intermediate duration studies are recorded in Table 2-2 and plotted in

Figure 2-2.

Chronic lethality data are available for NDMA-exposed rats, mice and

mink. Survival of rats that received 0.5 mg/kg/day of NDMA in the diet for

54 weeks (Terao et al. 1978) was not affected. Decreased survival occurred

in mice that were exposed to 0.43 mg/kg/day in the drinking water for life

(average 406 days) (Clapp and Toya 1970). Mink appear to be particularly

sensitive to NDMA as mortality resulted from ingestion of 0.1 mg/kg/day in

the diet for 321-670 days (Koppang and Rimeslatten 1976). The NOAEL value

and LOAEL values for lethality in these chronic duration studies are

recorded in Table 2-2 and plotted in Figure 2-2.

2.2.2.2 Systemic Effects

No studies were located regarding hematological, musculoskeletal or

dermal/ocular effects in humans or animals following oral exposure to NDMA.

Respiratory Effects. Petechial and larger hemorrhages were observed in

the lungs of two people following lethal poisoning with NDMA (Kimbrough

1982) (Section 2.2.2.1).

Macroscopic congestion was noted in the lungs of rats that were

administered 3.75 mg/kg/day doses of NDMA in the diet for l-12 weeks (Khanna

and Puri 1966). The adversity of the congestion cannot be determined because

results of lung histological examinations were not reported. No studies were
30

2. HEALTH EFFECTS

located regarding respiratory effects in animals due to chronic duration

oral exposure.

Cardiovascular Effects. Myocardial and endocardial bleeding was

observed in a person following lethal poisoning with NDMA (Kimbrough 1982)

(Section 2.2.2.1).

Macroscopic congestion was noted in the myocardium of rats that were

administered 3.75 mg/kg/day doses of NDMA in the diet for l-12 weeks (Khanna

and Puri 1966). The adversity of the congestion cannot be determined because

results of heart histological examinations were not reported. No studies

were located regarding cardiovascular effects in animals due to chronic

duration exposure.

Gastrointestinal Effects. Gastrointestinal hemorrhage occurred in

humans following lethal poisoning with NDMA (Kimbrough 1982, Pedal et al.

1982) (Section 2.2.2.1).

NDMA produced similar gastrointestinal effects in animals. Barnes and

Magee (1954) observed occasional hemorrhage into the gastrointestinal tract

in rats that died from treatment with a single 50 mg/kg dose of NDMA by

gavage , or with 10 mg/kg/day doses in the diet for 34-37 days. The numbers

of animals examined were unspecified (single dose study) or small (6 in the

diet study), and frequency of occurrence was not indicated. Gastrointestinal

hemorrhages were also observed in mink that ingested 0.32 or 0.63 mg

NDMA/kg/day via diet for 23-34 days (Carter et al. 1969). Only three mink

per dose were treated, the hemorrhages occurred in a total of three mink,

and the dose(s) that the affected mink received was not specified. The cause

of the hemorrhages in the mink was attributed to gastric and duodenal

erosions. No studies were located regarding gastrointestinal effects in

animals due to chronic duration exposure.

Hepatic Effects. Five members of a family who consumed unknown

quantities of NDMA in lemonade became ill with nausea and vomiting

associated with acute liver disease, generalized bleeding and low platelet

counts (Kimbrough 1982, Cooper and Kimbrough 1980). As indicated in Section

2.2.2.1, two of these people died; the other three were released from a

hospital 4-21 days after admission. Another fatality due to ingestion of

NDMA was attributed to liver failure (Fussgaenger and Ditschuneit 1980,

Pedal et al. 1982) (Section 2.2.2.1). Autopsies of the subjects described

above showed that the primary effects were hemorrhagic and cirrhotic changes

in the liver and necrosis and hemorrhage in other internal organs.

Hepatotoxicity of NDMA has been described and investigated in numerous

oral studies of acute, intermediate and chronic duration in several animal

species. Hepatotoxicity is the most prominent and characteristic systemic

effect of NDMA, resulting in centrilobular necrosis and hemorrhage often

leading to hemorrhagic ascites.
31

2. HEALTH EFFECTS

In acute studies, characteristic hepatotoxic alterations, as indicated

above, occurred in rats following single gavage doses as low as 20 and 8

mg/kg (Nishie 1983, Sumi and Miyakawa 1983), and following daily doses of

3.75 mg/kg in the diet for 1 or 2 weeks (Khanna and Puri 1966). These doses

therefore are LOAELs for serious hepatic effects. Jenkins et al. (1985)

observed degenerative alterations in the livers of rats following a single

2.5 mg/kg gavage dose of NDMA. As these alterations (collapse of reticulum

network in the centrilobular areas followed by regeneration) were

nonnecrotic and did not result in loss of the lobular architecture, the 2.5

mg/kg dose is a LOAEL for less serious hepatic effects. Single gavage doses

of 1.9 mg/kg and 0.7 mg/kg are a LOAEL for less serious hepatic effects and

a NOAEL, respectively, for rats, as nonnecrotic histologic alterations

(clumping and slight vacuolation of cells in the central vein area) occurred

at 1.9 mg/kg and no alterations occurred at 0.7 mg/kg (Korsrud et al. 1973),.

Daily gavage exposure to 5 mg/kg for 5-11 days produced hemorrhagic necrosis

in rats, guinea pigs, cats and monkeys (Maduagwu and Bassir 1980). Hamsters

that ingested daily doses of 4 mg/kg/day in the drinking water for 1, 2, 4,

7 or 14 days showed portal venopathy, a less serious hepatic effect (Ungar

1984). The NOAEL value and LOAEL values for hepatic effects in these acute

duration studies are recorded in Table 2-2 and plotted in Figure 2-2. The

rat diet dose of 3.75 mg/kg/day was calculated from the administered

concentration of 75 ppm in food (Khanna and Puri 1966); this concentration

is presented in Table l-4 for short-term exposure. The hamster drinking

water dose of 4 mg/kg/day was calculated from the administered concentration

of 20 ppm in water (Ungar 1984); this concentration is also presented in

Table l-4 for short-term exposure.

In intermediate duration studies with rats, characteristic hepatic

effects (described previously) were produced by treatment with NDMA doses of

3.75 mg/kg/day in the diet for 4-12 weeks (Khanna and Puri 1966), 5

mg/kg/day in the diet for 62-95 days (Barnes and Magee 1954), and 3.9

mg/kg/day in the diet for 40 weeks (Magee and Barnes 1956). Jenkins et al.

(1985) observed cirrhosis in rats that received 2.5 mg doses of NDMA by

gavage for 4 days/week for 9 weeks, but it is unclear if this is dose per kg

body weight or dose per total body weight. A dose of 1 mg/kg/day

administered by gavage for 30 days produced centrilobular congestion and

vacuolation of hepatocytes without necrosis in rats (Maduagwu and Bassir

1980), indicating that this dose is a LOAEL for less serious hepatic

effects. Hepatic alterations were not observed in rats treated with 2.5

mg/kg/day in the diet for 110 days (Barnes and Magee 1954). The NOAEL and

all LOAEL values for hepatic effects in rats from these intermediate

duration studies are recorded in Table 2-2 and plotted in Figure 2-2.

Characteristic liver alterations (described previously) occurred in

mice that were treated with NDMA doses of 5.0 mg/kg/day in the drinking

water for l-4 weeks (Anderson et al. 1986), 13 mg/kg/day in the diet for 16-

92 days (Otsuka and Kuwahara 1971) and 5.26 mg/kg/day in the diet for 5

months (Takayama and Oota 1965). These LOAELs for hepatic effects in mice

due to intermediate duration exposure are included in Table 2-2 and plotted
32

2. HEALTH EFFECTS

in Figure 2-2. The mouse dose of 5.26 mg/kg/day was calculated from the

administered concentration of 50 ppm in food (Takayama and Oota 1965); this

concentration is presented in Table 1-4 for long-term exposure.

Liver effects resulting from intermediate duration oral exposure have

been observed in species .other than rat and mouse. Treatment with 1

mg/kg/day by gavage for 30 days was hepatotoxic for guinea pigs, cats and

monkeys (Maduagwa and Basir 1980). Necrotic alterations occurred in dogs

treated with 2.5 mg/kg by capsule on 2 days/week for 3 weeks (Strombeck et

al. 1983). Fibrotic and proliferative alterations without necrosis or

hemorrhage were observed in rabbits treated with an average NDMA dose of 1.6

mg/kg/day in the diet for 22 weeks (Magee and Barnes 1956), indicating that

this dose is a less serious LOAEL for hepatic effects. Occlusive alterations

in the portal veins developed in hamsters that received daily 4 mg/kg doses

in the drinking water for 28 days or 8, 12 or 16 weeks (Ungar 1984, 1986),

indicating that this dose is also a less serious LOAEL for hepatic effects.

Similar hepatic venopathy occurred in mink exposed to 0.13-0.15 mg/kg/day in

the diet for 122 days (Koppang and Rimeslatten 1976). Mink that were given

doses of 0.32 or 0.63 mg/kg/day in the diet for 23-34 days had widespread

liver necrosis (Carter et al. 1969), but low numbers of animals were tested

(three per dose). Liver necrosis was also observed in mink that ingested

0.18 mg/kg/day via diet (Martin0 et al. 1988); limitations of this study,

discussed in Section 2.2.2.1, include uncertainty regarding exposure

duration and concentration. All reliable LOAEL values for hepatic effects

due to intermediate duration exposure in these studies are recorded in

Table 2-2 and plotted in Figure 2-2. The hamster drinking water dose of 4

mg/kg/day was calculated from the administered concentration of 20 ppm in

water (Ungar 1984, 1986); this concentration is presented in Table 1-4 for

long-term exposure. It should be noted that this water concentration (20

ppm) is higher than the water concentration associated with death (5.5 ppm)

due to long-term exposure reported in Table 1-4. The apparent discrepancy in

these values is attributable to differences in species sensitivity and

length of exposure (rats exposed for 30 weeks, hamsters exposed for 28

days).

In chronic duration studies, characteristic hepatotoxic alterations

(described previously) were not observed in rats that were treated with 0.5

mg/kg/day NDMA in the diet for 54 weeks (Terao et al. 1978) or 96 weeks

(Arai et al. 1979). Alterations in mink that ingested 0.1 mg/kg/day doses of

NDMA in the diet for 321-670 days included occlusive changes in the hepatic

veins with focal necrosis (Koppang and Rimeslatten 1976). Data regarding

hepatic effects of chronic oral NDMA exposure in other species were not

found in the available literature. The NOAEL values and LOAEL value for

hepatic effects due to chronic exposure in these studies are recorded in

Table 2-2 and plotted in Figure 2-2.

Although hepatotoxicity is the primary effect of NDMA and has been

demonstrated in all tested species, calculation of MRLs for NDMA is

precluded by insufficient data defining the threshold region (i.e., NOAELs)
33

2. HEALTH EFFECTS

for intermediate and chronic exposures, particularly for species which

appear to be particularly sensitive (e.g., mink) and because serious effects

(perinatal death) occurred in a developmental study (see Section 2.2.2.5) at

a dose lower than any NOAELS for liver effects.

Renal Effects. No studies were located regarding renal effects in

humans following oral exposure to NDMA.

Limited information is available regarding renal effects of

orallyadministered NDMA in animals. In a study by Nishie (1983), pregnant and

nonpregnant rats were treated with a single NDMA dose of 15 or 20 mg/kg/day

by gavage. An unspecified number of deceased animals (dose and pregnancy

state not indicated) had distal tubule necrosis two days following

treatment, and surviving rats had normal kidneys. Macroscopic congestion was

noted in kidneys of rats that were administered 3.75 mg/kg/day doses of NDMA

in the diet for l-12 weeks (Khanna and Puri 1966). The adversity of the

congestion cannot be determined because results of kidney histological

examinations were not reported. Moderate tubule congestion with other

effects (glomerulus dilatation, slightly thickened Bowman's capsule) were

observed in mink that ingested 0.18 mg/kg/day via diet (Martin0 et al.

1988); limitations of this study, discussed in Section 2.2.2.1, include

uncertainty regarding exposure duration and concentration.

Other Systemic Effects. Adrenal relative weight and mitotic count were

increased in rats following a single 20 mg/kg gavage dose of NDMA (Nishie et

al. 1983). Other results of the adrenal histological examinations were not

described, precluding assessment of adversity of the increased adrenal

weight, There was no effect on thyroid weight or histology in the same

study. It therefore is appropriate to regard 20 mg/kg as a NOAEL for

thyroid effects in rats due to acute oral exposure (Table 2-2 and Figure

2-2). Macroscopic congestion was noted in spleens of rats that were

administered 3.75 mg/kg/day doses of NDMA in the diet for l-12 weeks (Khanna

and Puri 1966). The adversity of the congestion cannot be determined because

results of spleen histological examinations were not reported.

2.2.2.3 Immunological Effects

No studies were located regarding immunological effects in humans

following oral exposure to NDMA.

Limited information is available regarding immunological effects of

orally-administered NDMA in animals. Skin graft survival time and white

blood cell count were not reduced in rats that received a single 40 mg/kg

dose of NDMA by gavage, indicating that treatment was not immunosuppressive

(Waynforth and Magee 1974). The dose reported was near the LD50 for rats,

but all of the animals died by day 21; it is indicated that the high

mortality may partially reflect the stress of skin graft rejection. Although

treatment resulted in 100% mortality, this dose represents a NOAEL for

immunological effects due to acute duration oral exposure (Table 2-2 and
34

2. HEALTH EFFECTS

Figure 2-2). No studies were located regarding immunological effects in

animals following intermediate or chronic duration exposure to NDMA.

2.2.2.4 Neurological Effects

No studies were located regarding neurological effects in humans

following oral exposure to NDMA.

Dogs treated with 2.5 mg NDMA/kg/day by capsule on 2 consecutive

days/week for 3 weeks experienced marked central nervous system (CNS)

depression (Strombeck et al. 1983). The significance of this observation

cannot be ascertained since it was not characterized further. As these dogs

developed liver necrosis and hepatic insufficiency, it is possible that the

CNS depression is secondary to liver damage rather than a direct

neurological effect of NDMA.

2.2.2.5 Developmental Effects

No studies were located regarding developmental effects in humans

following oral exposure to NDMA.

Evidence indicates that orally-administered NDMA is a developmental

toxicant in animals. Fetuses of rats that received single 20 mg/kg doses of

NDMA by gavage on days 15 or 20 of gestation had significantly decreased

body weights, but fetal survival data were not reported (Nishie 1983). This

dose was also toxic to the dams as indicated by reduced body weight,

hepatotoxicity and mortality. Other investigators have reported fetal

mortality in rats that were treated with a single 30 mg/kg dose of NDMA by

gavage on various days during the first 12 days (Aleksandrov 1974) or 15

days (Napalkov and Alexandrov 1968) of gestation. In other studies, NDMA

reportedly caused fetal deaths in rats when administered in the diet at a

dose of 5 mg/kg/day from an unspecified day in early pregnancy (treatment

duration not indicated) (Bhattacharyya 1965), by gavage at a dose of 2.9

mg/kg/day during the first or second weeks of gestation (Napalkov and

Alekandrov 1968), or by gavage at a dose of 1.4 mg/kg/day throughout

gestation until days 17-21 (not specified) (Napalkov and Alekandrov 1968).

Teratogenic effects were not observed in the studies of Aleksandrov (1974)

and Napalkov and Alekandrov (1968), and not eva1uated.i.n the studies of

Nishie (1983) and Bhattacharyya (1965). Evaluation of the studies of

Bhattacharyya (1965), Napalkov and Alekandrov (1968) and Aleksandrov (1974)

is complicated by insufficient information regarding experimental design and

results; deficiencies include lack of control data, lack of maternal

toxicity data, use of pooled data and/or uncertain treatment schedule. Due

to these limitations, there is low confidence in the doses associated with

fetotoxicity in these studies. As Nishie (1983) is the only adequately

reported fetotoxicity study, 20 mg/kg is presented as a LOAEL for

developmental effects in rats due to acute exposure to NDMA in Table 2-2 and

Figure 2-2.
35

2. HEALTH EFFECTS

In another experiment conducted by Aleksandrov (1974), a single dose of

30 mg NDMA/kg was administered by gavage to rats on day 21 of gestation.

Histological examination of the offspring at the time of natural death (•274

days after exposure) reportedly showed tumors in 5 of 20 animals. Although

this is possibly a manifestation of transplacental carcinogenesis,

evaluation of this finding is precluded by limitations including a lack of

control data and inadequate reporting of tumor types.

Increased perinatal mortality (stillbirths and newborn deaths) occurred

in mice as a consequence of maternal treatment with 0.02 mg NDMA/kg/day in

the drinking water (Anderson et al. 1978). The mice were treated for 75 days

prior to mating and throughout pregnancy and lactation. Histological

examinations of the stillborn fetuses and dead neonates showed no

abnormalities. The 0.02 mg/kg/day dose represents a LOAEL for developmental

effects due to intermediate duration exposure (Table 2-2 and Figure 2-2).

2.2.2.6 Reproductive Effects

No studies were located regarding reproductive effects in humans

following oral exposure to NDMA.

There was no significant increase in time-to-conception in mice that

were exposed to 0.02 mg NDMA/kg/day via drinking water for 75 days prior to

mating (Anderson et al. 1978). Other reproductive indices were not

evaluated.

2.2.2.7 Genotoxic Effects

Methylated DNA (7-methylguanine and O6

 -methylguanine) was detected in

the liver of a victim of suspected NDMA poisoning (Herron and Shank 1980).

Additional studies regarding genotoxic effects in humans following oral

exposure to NDMA were not located.

Oral studies with rats indicate that the liver is sensitive to the

genotoxic effects of NDMA. When administered by gavage at a dose of 5.2

mg/kg, NDMA induced damage in rat liver DNA as measured by increased

alkaline elution (Brambilla et al. 1981). When administered to rats via

diet at a dose of 2.5 mg/kg/day, NDMA induced DNA damage in the liver as

measured by a slow sedimentation in alkaline sucrose gradients (Abanobi et

al. 1979). The effect was first observed after 2 days of feeding, and

became progressively worse during the next 8 weeks of feeding; no

proportionate increases in damage occurred when the feedings were continued

for 15 or 31 weeks. DNA synthesis and repair was detected in the liver of

rats treated with single 10 or 50 mg/kg doses by gavage (Bermudez et al.

1982). Radiolabeled thymidine uptake during mouse testicular DNA synthesis

was inhibited by a single gavage dose of 50 mg NDMA/kg (Friedman and Staub

1976).
36

2. HEALTH EFFECTS

Administration of NDMA to hamsters by gavage at doses of 50, 100, or

200 mg/kg on the 11th or 12th day of pregnancy caused micronucleus formation

and chromosomal aberrations in the embryonic fibroblasts (Inui et al. 1979).

NDMA did not induce significant increases in sister chromatid exchanges in

bone marrow cells of Chinese hamsters following gavage administration of

12.5-400 mg/kg (Neal and Probst 1983).

2.2.2.8 Cancer

No studies were located regarding carcinogenic effects in humans

following oral exposure to NDMA.

The carcinogenicity of orally-administered NDMA has been demonstrated

unequivocally in acute, intermediate and chronic duration studies with rats,

mice, hamsters and mink. The liver and lungs are the primary targets for

NDMA carcinogenesis but tumors of the kidneys and testes can also occur.

Incidences of liver and lung tumors are generally very high (often 50-100%),

but liver tumors appear to occur most frequently in rats and hamsters and

lung tumors appear to occur most frequently in mice. The liver tumors are

usually hemangiosarcomas and hepatocellular carcinomas, and lung tumors are

usually adenomas and liver tumor metastases.

Low incidences of epithelial tumors (8.6%) and mesenchymal tumors

(14.5%) developed in the kidneys of rats following treatment with 8 mg

NDMA/kg/day for 6 days (McGiven and Ireton 1972, Ireton et al. 1972).

Evaluation of these data is complicated by the lack of a control group.

Daily diet treatment with 9.5 mg/kg for one week produced kidney and lung

adenomas in mice (Terracini et al. 1966). No other acute duration oral

carcinogenicity studies were found in the reviewed literature. The CEL from

the mouse study is presented in the acute duration category in Table 2-2 and

in Figure 2-2.

Numerous oral carcinogenicity studies of NDMA of intermediate duration

have been conducted. Treatment durations were often in the range of 20-40

weeks, frequency of treatment ranged from once weekly to daily, and

carcinogenicity was observed in all studies. Studies representing various

treatment durations and various methods of oral treatment (drinking water,

diet and gavage) for the lowest doses in different species are identified

below.

Rats administered NDMA in the drinking water at doses of 0.3

mg/kg/day, 5 days/week for 30 weeks, developed malignant liver tumors

(Keefer et al. 1973, Lijinsky and Reuber 1984). Lijinsky et al. (1987)

observed high incidences of liver, lung and kidney tumors in rats that were

treated by gavage with 6 mg NDMA/kg twice weekly for 30 weeks; controls were

not used in this study. In an intermediate duration diet study with rats,

daily treatment with a dose of 3.9 mg/kg for 40 weeks resulted in a 95%

incidence of hepatic tumors (Magee and Barnes 1956). The CELs from these
37

2. HEALTH EFFECTS

intermediate duration studies with rats are recorded in Table 2-2 and

plotted in Figure 2-2.

Liver, lung and/or kidney tumors developed in mice that were exposed to

NDMA daily via drinking water at doses of 1.8 mg/kg for 49 days (Clapp and

Toya 1970), 1.19 mg/kg for 38 weeks (Terracini et al. 1966) and 0.4 mg/kg

for 224 days (Clapp and Toya 1970). Daily administration of NDMA via diet at

doses of 13 mg/kg for 16-92 days (Otsuka and Kuwahara 1971), 5.26 mg/kg for

5 months (Takayama and Oota 1965) and 9.04 mg/kg for 10 months (Takayama and

Oota 1965) also induced liver, lung and/or kidney tumors in mice. In the

only intermediate duration gavage study with mice, twice weekly doses of 1

mg/kg for 50 weeks resulted in high (37-53%) incidences of malignant liver

tumors (Griciute et al. 1981). The CELs from these intermediate duration

studies with mice are recorded in Table 2-2 and plotted in Figure 2-2.

Hamsters that were treated with NDMA by gavage twice weekly with a dose

of 5.4 mg/kg for 6.5 weeks, once weekly with a dose of 10.7 mg/kg for 4

weeks, or once weekly with a dose of 5.4 mg/kg for 20 weeks developed high

(60-79%) incidences of liver tumors (Lijinsky et al. 1987). However, control

groups were not included in the study of Lijinsky et al. (1987). Daily

administration of 4 mg/kg in the drinking water to hamsters for 12 or 16

weeks resulted in high incidences of cholangiocellular adenocarcinomas

(Ungar 1986). The CELs from these intermediate duration studies with

hamsters are recorded in Table 2-2 and plotted in Figure 2-2. Hemangiomatous

liver tumors occurred in 55% of deceased mink that received NDMA in the diet

at an estimated dose of 0.18 mg/kg/day (Martin0 et al. 1988); limitations of

this study, discussed in Section 2.2.2.1, include uncertainty regarding

exposure duration and concentration, examination only of animals that died

and use of historical controls. Due to the limitations of this study, it is

inappropriate to present a CEL for mink due to intermediate duration

exposure in Table 2-2 and Figure 2-2.

Chronic oral carcinogenicity studies of NDMA have been conducted with

rats, mice and mink. Tumors at sites other than the liver and testis have

not been associated with chronic treatment. Terao et al. (1978) observed a

47% increase in the incidence of testicular Leydig-cell tumors, but no

tumors in the liver or other tissues, in rats that were treated with 0.5

mg/kg daily doses of NDMA in the diet for 54 weeks. Increased incidences of

liver tumors, but not testicular interstitial cell tumors, occurred in rats

that received 0.05 or 0.5 mg/kg/day doses of NDMA in the diet for 96 weeks

(Arai et al. 1979). In this study, liver tumor incidences were generally

higher in female rats than in male rats. Increased incidences of liver

tumors also occurred in rats that were treated with NDMA in the diet for 96

weeks at a dose of 10.0 mg/kg/day (Ito et al. 1982); similar treatment with

doses of 0.1 or 1.0 mg/kg/day did not produce increased incidences of liver

tumors. It should be noted that Wistar rats were tested in both the Ito et

al. (1982) and Arai et al. (1979) studies. The reason for the lack of liver

tumors at doses below the relatively high 10 mg/kg/day dose in the Ito et

al. (1979) study is not clear, but may be related to low susceptibility of
38

2. HEALTH EFFECTS

male rats. In a lifetime drinking water study, Peto et al. (1984)

administered doses of 0.001-1.2 mg/kg/day to rats and observed that

incidences of liver tumors were significantly increased at ≥0.02 mg/kg/day;

median survival time at the lowest tumorigenic doses was in the range of 28-

31 months. Crampton (1980) administered NDMA to rats in the drinking water

at doses ranging from 0.002-1.5 mg/kg/day for life and observed increased

liver tumor incidences at ≥0.008 mg/kg/day; median survival time at 0.008

mg/kg day was >900 days. The results reported by Crampton (1980) were

preliminary and there is uncertainty regarding the dosages; ppm

concentrations in water and mg/kg/day equivalency were reported, but the

basis for the equivalency is not indicated and the conversion cannot be

verified using standard methodology. Clapp and Toya (1970) administered NDMA

to mice via drinking water at daily doses of 0.43 and 0.91 mg/kg/day for

life and observed that incidences of lung tumors and liver hemangiosarcomas

were significantly increased at both doses; mean survival time at the low

and high doses were 12 and 17 months, respectively. Hemangiomatous liver

tumors developed in mink exposed to 0.1 mg/kg/day NDMA in the diet for 321-

607 days (Koppang and Rimeslatten 1976). The CELs for rats, mice and mink

from these chronic studies, except the uncertain value from the Crampton

(1980) study, are recorded in Table 2-2 and plotted in Figure 2-2.

The EPA (1988a) has derived and verified an oral slope factor (BH) of

51 (mg/kg/day)-l for NDMA based on the liver tumor response in the Peto et

al. (1984) study. Using this slope factor, the doses associated with upper

bound lifetime cancer risk levels of 10-4 to 10-7 are calculated to be 1.96

x 10-6 to 1.96 x 10-9 mg/kg/day, respectively. The cancer risk levels are

plotted in Figure 2-2.

2.2.3 Dennal Exposure

2.2.3.1 Death

No studies were located regarding lethality in humans or animals

following dermal exposure to NDMA.

2.2.3.2 Systemic Effects

No studies were located regarding systemic effects in humans following

dermal exposure to NDMA. Limited information was located regarding systemic

effects in animals following dermal exposure; no animal studies provided

information on respiratory, cardiovascular, gastrointestinal, hematological,

musculoskeletal, hepatic or renal effects.

Dermal/Ocular Effects. Small ulcerations and scarring of the skin were

observed in hairless mice that were treated once weekly with topical doses

of 33.3 mg NDMA/kg for 20 weeks (Iversen 1980). No studies were located

regarding NDMA-related ocular effects in animals.
39

2. HEALTH EFFECTS

Other Systemic Effects. Barnes and Magee (1954) noted that daily

application of 100 mg NDMA/kg to rats for 4 days had no effect on general

condition.

No studies were located regarding the following effects in humans or

animals following dermal exposure to NDMA:

2.2.3.3 Immunological Effects

2.2.3.4 Neurological Effects

2.2.3.5 Developmental Effects

2.2.3.6 Reproductive Effects

2.2.3.7 Genotoxic Effects

2.2.3.8 Cancer

No studies were located regarding carcinogenic effects in humans

following dermal exposure to NDMA.

A low incidence of lung adenomas (13%), but no skin tumors, developed

in hairless mice that were treated once weekly with 33.3 mg/kg topical doses

of NDMA for 20 weeks (Iversen 1980). Lung and skin tumors were not observed

in historical control groups. Although Iversen (1980) concluded that the

lung cancers were related to the topical applications of NDMA, it should be

noted that the mice were housed 8 to a cage and could have licked the NDMA

off each other or inhaled the compound due to its volatility.

2.3 RELEVANCE TO PUBLIC HEALTH

Death. Oral LD50 values of 23 and 40 mg NDMA/kg have been reported for

pregnant and nonpregnant rats, respectively (Nishie 1983, Druckrey 1967).

Oral LD5Os have not been determined for NDMA in other species. LD5Os for

single doses of NDMA administered by intraperitoneal injection have also

been reported; these values are consistent with the oral LD5Os and include

26.5 mg/kg in rats (Barnes and Magee 1954), 42.7 mg/kg in rats (Heath 1962)

and 19 mg/kg in mice (Friedman and Sanders 1976). Repeated oral exposure to

NDMA resulted in decreased survival in rats, mice and all other species that

have been tested. In general, doses ranging from approximately 0.1-5

mg/kg/day have produced death in animals after several days to several

months of exposure. Variations in lethal doses appear to be attributable

more to intraspecies differences than differences in frequency or method of

oral treatment. With the exception of mink, there do not appear to be marked

differences in sensitivity among the species that have been tested. Deaths

resulting from a single exposure or repeated exposures for several days or

several weeks are generally attributed to liver toxicity; deaths associated
40

2. HEALTH EFFECTS

with longer duration (e.g., 20-40 weeks) exposures are due to liver tumor

development.

In general, lethal doses,of NDMA and causes of death are similar among

animal species. Human fatalities due to ingestion or inhalation of NDMA were

also attributed to liver toxicity but adequate dose information is not

available.

Systemic Effects. Hepatotoxicity is the primary systemic effect of

NDMA. Hepatotoxicity has been demonstrated in all animal species that have

been tested, and has been observed in humans who were exposed to NDMA by

ingestion or inhalation. The characteristic hemorrhagic necrosis caused by

NDMA are particularly prevalent following exposure to acutely toxic single

doses or repeated doses for short durations. Liver tumors are the

predominant effect of longer duration exposures. The mechanism of NDMAinduced

liver toxicity is not clearly understood but may be related to

alkylation of cellular protein (Barnes and Magee 1954, Magee et al. 1976,

Diaz Gomez et al. 1981, 1983, Martin0 et al. 1988).

Although the hepatotoxicity of NDMA has been established unequivocally

in numerous acute, intermediate and chronic duration oral studies with

animals, relatively few of the studies delineate dose-response relationships

and appropriate information regarding thresholds for this effect is not

available. As noted for lethality, reported hepatotoxic doses for all

species occur in the same general range with variations attributable more to

intraspecies differences than treatment schedule or method. Human fatalities

due to oral and inhalation exposure to NDMA have been reported in which

hemorrhagic, necrotic and cirrhotic alterations in the liver were observed,

indicating that NDMA produces similar hepatic effects in humans and animals.

Therefore it is reasonable to expect that NDMA also will be hepatotoxic in

humans at sublethal doses.

Limited information is available regarding nonhepatic systemic effects

of NDMA in humans. This information has been obtained from autopsies of

victims accidentally exposed to NDYA vapors or poisoned after ingestion of

NDMA. The effects can be described as a general bleeding tendency.

Hemorrhages have been noticed in the gastrointestinal tract, heart,

respiratory system and brain (Freund 1937; Kimbrough 1982). The mechanism by

which NDMA could induce bleeding is not known, but the bleeding tendency

could be a consequence of decreased formation of clotting factors resulting

from liver damage, impairment of the clotting mechanism or decreased number

or function of platelets. Jacobson et al. (1955), for example, showed that

NDMA greatly increases prothrombin time in dogs exposed to NDMA by

inhalation. It is also possible that hemorrhagic effects could be caused by

effects of NDMA on tissues. Because of its irritant properties, it is not

difficult to explain the occurrence of hemorrhages in tissues that have

direct contact with NDMA (gastrointestinal bleeding after oral ingestion, or

bleeding of the bronchi and trachea after inhalation). However, it remains

unknown why gastrointestinal bleeding can occur following inhalation
41

2. HEALTH EFFECTS

exposure. An alternative explanation could be that NDMA has a direct effect

on the blood vessels. In fact, Ungar (1984, 1986) showed that oral treatment

of hamsters with NDMA induced fragmentation of elastic fibers in portal

vessels as well as denudation of the portal endothelium. Furthermore,

autopsy of a victim of acute NDMA poisoning showed that "the central hepatic

veins had lost their endothelial'lining cells" (Kimbrough 1982).

There is a relative paucity of information for nonhepatic systemic

effects in animals because the emphasis of most studies was on

hepatotoxicity or cancer, for which the liver is the primary target organ.

Nonhepatic systemic effects that have been reported include gastrointestinal

hemorrhage and congestion of several organs (kidney, lung, heart, spleen) in

rats and/or mink, but the prevalence of these effects cannot be determined

because these sites were examined infrequently.

Immunological Effects. A single oral dose of NDMA near the oral LD50

did not reduce humoral immune response in rats, but a single intraperitoneal

dose near the intraperitoneal LD50 reduced humoral immune response in mice

(Waynforth and Magee 1974). A number of other recent studies have found that

NDMA given by intraperitoneal injection alters humoral immunity and

antibody-mediated host defense mechanisms (Kaminski et al. 1989; Thomas

et al. 1985, Myers et al. 1986, 1987, Scherf and Schmahl 1975, Holsapple et

al. 1983, 1984, 1985, Johnson et al. 1987a,b). Immunosuppression resulting

from NDMA exposure is not believed to be a result of direct interaction

between the reactive intermediaries of NDMA and splenic lymphocytes, thereby

indicating a difference between the mechanisms of immunotoxicity and

carcinogenicity/genotoxicity (Holsapple et al. 1984). In vivo studies have

shown that NDMA modulates the cellular immune response by altering the

production and/or maturation/differentiation of bone marrow stem cells into

functional macrophages (Myers et al. 1986, 1987). In vitro tests identify

the primary cell target of NDMA as the B-lymphocyte (Holsapple et al. 1984,

1985). Thus, it is likely that NDMA decreases the overall reactivity of both

T- and B-lymphocytes. It is not known whether NDMA is likely to be

immunosuppressive in humans.

Developmental Effects. NDMA was fetotoxic to rats at oral doses that

were toxic to the mother. Limited data indicate that these doses were not

teratogenic for the rats. Oral administration of NDMA to mice resulted in

increased perinatal deaths without histological abnormalities. It is not

known whether NDMA could cause developmental effects in humans, but it cou

be a potential developmental toxicant at doses which are toxic to pregnant

women.

Reproductive Effects. Mice that were exposed to NDMA in drinking water

prior to mating and during pregnancy and lactation showed an increase in the

frequency of perinatal death among their offspring. Based on these data,

NDMA could be considered a potential human reproductive toxicant.
42

2. HEALTH EFFECTS

Genotoxic Effects. Several in vitro studies have examined genotoxic

effects of NDMA in human cells. As indicated in Table 2-3, NDMA induced DNA

repair and synthesis in human lymphoblasts, and sister chromatid exchange

in human lymphocytes and fibroblasts.

Genotoxicity of NDMA has been demonstrated consistently in numerous in

vitro studies with non-human systems. As indicated in Table 2-3, NDMA was

mutagenic in bacteria (Salmonella tvnhimurium, Escherichia coli), yeast

(Saccharomvces cerevisiae), and mammalian cells (Chinese hamster V79 and

ovary cells and mouse lymphoma L5178Y cells). NDMA induced unscheduled DNA

synthesis and DNA repair and synthesis in rat, mouse and hamster

hepatocytes. Treatment-related DNA fragmentation occurred in rat and human

hepatocytes. Chromosomal aberrations occurred in Chinese hamster primary

lung cells, rat ascites hepatoma cells, and rat esophageal tumor cells.

Sister chromatid exchanges occurred in Chinese hamster ovary cells, Chinese

hamster primary lung cells, human lymphoblasts and fibroblasts, and rat

esophageal tumor and ascites hepatoma cells.

In vivo studies (Table 2-4) have shown that NDMA methylates DNA, causes

DNA fragmentation and induces DNA synthesis and repair in liver and other

tissues of various species (e.g., rat, mouse, hamster, gerbil). NDMA

induced chromosomal aberrations in hamster embryonic fibrolasts, sister

chromatid exchanges in mouse bone marrow cells, and micronuclei in rat

hepatocytes and rat and mouse bone marrow cells. The genotoxic effects

indicated above occurred after inhalation, oral or intraperitoneal

administration of NDMA. Sperm abnormalities were not seen in mice following

intraperitoneal administration of NDMA. Sex linked recessive lethal

mutations occurred in Drosophila melanogaster, which indicates potential

heritable mutagenicity of NDMA.

The weight of evidence indicates that NDMA is genotoxic in mammalian

cells. In vitro studies with human cells, as well as in vitro and in vivo

studies with animals and microbes, support this conclusion. Given the type

and weight of genotoxicity evidence, it is appropriate to predict that NDMA

poses a genotoxic threat to humans.

Cancer. The oral carcinogenicity of NDMA has been demonstrated in

numerous studies with various species of animals. Inhalation exposure to

NDMA has been reported to be carcinogenic to rats and mice in two studies.

The carcinogenicity of NDMA is also documented in numerous single and or

weekly subcutaneous and intraperitoneal injection studies, and in studies in

which NDMA was administered prenatally and to newborn animals. Many of the

carcinogenicity studies of NDMA were conducted specifically to induce cancer

for various purposes, such as investigations of structure-activity

relationships and pathogenesis. Tumors in tissues other than the liver and

respiratory system (e.g., kidney, testis) have not been observed often in

many of the carcinogenicity studies; this appears to be attributable in part

to limited examination of nonhepatic tissues.



46

2. HEALTH EFFECTS

There is increasing evidence, derived from in vitro and in vivo

metabolic studies, indicating that the carcinogenic effects of NDMA are due

to a metabolite rather than the compound itself (Singer 1979). NDMA is

converted into an alkylating (methylating) agent after metabolism by

microsomal mixed-function oxidases. This process occurs principally in the

liver and to a lesser extent in kidney and lungs, and results in the

methylation of cellular macromolecules such as DNA, RNA and other proteins.

Methylation occurs at several positions in DNA including N-l, N-3 or N-7 of

deoxyadenosine; N-3, N-7 or 06

 of deoxyguanosine; N-3 of deoxycytidine; and

02

 or 04 of thymidine. Experimental evidence indicates that methylation at

the 06-position of guanine may be responsible for the carcinogenic activity

of nitrosamines in general, however, the carcinogenic potential of other

methylated products cannot be ruled out. The methylation of DNA by NDMA has

been studied extensively (e.g., Bamborschke et al. 1983, O'Connor et al.

1982, Pegg et al. 1981, Pegg and Hui 1978, Stumpf et al. 1979.).

The carcinogenic properties of NDMA, and nitrosamines in general, have

been extensively studied. It is of considerable interest that, despite its

ubiquitous distribution, NDMA induces tumors in a limited number of organs

and tissues and that there are marked differences in this response among

animal species. Differences in pharmacokinetics properties seem to play an

important role in the carcinogenic action of NDMA (Pegg 1980, Lijinsky

1987). For example, the degree of hepatic extraction from the portal blood

seems to determine whether tumors develop in extrahepatic sites. Therefore,

large doses of NDMA tend to induce extrahepatic tumors (spill-over effect).

In addition, metabolic activating systems and repair mechanisms may not

operate at the same rates in different organs and different species. Route

of administration also seems to be a factor in NDMA carcinogenesis since

different responses are seen in a particular species when different routes

of exposure are used. This suggests that rates of absorption can determine

the site of tumor development.

Based on the unequivocal evidence of carcinogenicity in animals, it is

reasonable to anticipate that NDMA will be carcinogenic in humans. It is

important to recognize that this evidence also indicates that oral exposures

of acute and intermediate duration are sufficient to induce cancer.

2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS

A considerable amount of DNA methylation in the liver of a suspected

NDMA poisoning case was reported by Herron and Shank (1980). Based on

studies in rats, in which the amount of DNA alkylation could be correlated

with known amount of orally administered NDMA, the authors estimated that

the victim had been exposed to a dose of 20 mg/kg or more of NDMA. No other

studies were located regarding levels of NDMA or its metabolites in human

tissues and fluids associated with effects. Several analytical methods have

been developed to determine levels of NDMA in human tissues and fluids.

These methods are described in Chapter 6.
47

2. HEALTH EFFECTS

2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN TISSUES

AND/OR HEALTH EFFECTS

Although data relating specific amounts of NDMA in the environment

with levels in human tissues and/or health effects have not been reported,

some qualitative information is available. This information, given below,

has to be interpreted with caution since results were not always rigorously

reported or evaluated, and endogenous formation of NDMA was not quantitated.

A high incidence of nasopharyngeal carcinoma was found in Tunisia

(North Africa), Southern China and Greenland among populations who consume

foods with a high content of volatile nitrosamines (Poirier et al. 1987). Lu

et al. (1987) found a positive correlation between the amount of NDMA and

other nitrosamines in the gastric juice of Chinese with a high incidence of

esophageal carcinoma. Wild et al. (1987) observed a positive relationship

between levels of 06

-methyldeoxyguanosine (implicated in the initiating

process of nitrosamine-induced cancer) and incidences of esophageal and

stomach cancer in the province of Lin-xian, China. Yu and Henderson (1987)

reported finding a high incidence of nasopharyngeal carcinoma in individuals

from Hong Kong, who are known to consume from early in life considerable

amounts of Cantonese-style salted fish, which has a high content of NDMA and

other nitrosamines.

2.6 TOXICOKINETICS

2.6.1 Absorption

2.6.1.1 Inhalation Exposure

No studies were located regarding the rate and extent of absorption of

NDMA following inhalation exposure of humans or animals to NDMA. However, it

can be inferred that NDMA is absorbed from the air since it can be detected

in the urine of rats (Klein and Schmezer 1984) and dogs (Raabe 1986) after

inhalation exposure. Absorption is also indicated by reports of human

deaths following inhalation of NDMA (see Section 2.2.1.1).

2.6.1.2 Oral Exposure

No studies were located regarding the absorption of NDMA following

oral exposure of humans.

The absorption of NDMA from the gastrointestinal tract of animals is

fast. Less than 2% of the labelled compound could be recovered from the

gastrointestinal tract 15 minutes after oral administration of 14C-NDMA to

rats (Diaz Gomez et al. 1977). Absorption seems to be independent of the

dose administered (Diaz Gomez et al. 1972). In the rat, NDMA is absorbed

much faster from the small intestine than from the stomach, in isolated

preparations (Heading et al. 1974) and in vivo (Pegg and Perry 1981).
48

2. HEALTH EFFECTS

Ishiwata et al. (1977) reported that the disappearance curve of NDMA from

isolated guinea pig stomach and small intestine follows first order

kinetics.

2.6.1.3 Dermal Exposure

No studies were located regarding the absorption of NDMA following

dermal exposure of humans.

Indirect evidence indicating that NDMA may be absorbed through the

skin was found in a study published by Iversen (1980) in which topical

application of NDMA induced lung adenomas in mice. The results from

Iversen, however, should be interpreted with caution since the mice were

housed 8 to a cage and could have licked the NDMA from each other and also

could have inhaled this volatile compound.

2.6.2 Distribution

Unmetabolized NDMA was found to be evenly distributed among the main

organs of mice and rats shortly after i.v. injection to animals in which the

metabolism of NDMA had been inhibited (Magee 1956; Johansson and Tjalve

1978). Wishnok et al. (1978) reported a similar finding in rats following

i.p. injections. Johnson et al. (1987a) reported that one hour after a dose

of 6 mg 14C-NDMA/kg was administered by intraperitoneal injection to mice,

the liver contained two times as much radioactivity as the kidney, spleen

and thymus.

2.6.2.1 Inhalation Exposure

No studies were located regarding the distribution of NDMA following

inhalation exposure of humans or animals.

2.6.2.2 Oral Exposure

No studies were located regarding the distribution of NDMA following

oral exposure of humans.

Daugherty and Clapp (1976) reported that 15 minutes after oral

administration of 14C-NDMA to mice, the relative amounts of radioactivity in

the homogenates of heart, forestomach, esophagus, liver and lung were 1, 2,

3, 10 and 70, respectively. The differences could be attributed to different

tissue affinity, transport and/or metabolism. Measurable amounts of NDMA

were reported in blood, liver, kidney, lungs and brain of mice exposed to 5

mg NDMA/kg/day in drinking water.for up to 4 weeks (Anderson et al. 1986).

NDMA has been detected in maternal blood, placenta, fetus and amniotic

fluid of pregnant Syrian hamsters for up to 2 hours after a single

subcutaneous dose of 12.5 mg/kg of the chemical (Althoff et al. 1977).
49

2. HEALTH EFFECTS

Liver and kidney DNA from 14-day-old rats became labelled after treating the

nursing mothers with 14C-NDMA by gavage (Diaz Gomez et al. 1986).

2.6.2.3 Dermal Exposure

No studies were located regarding the distribution of NDMA following

dermal exposure of humans.

The study by Iversen (1980), in which lung adenomas were noticed in

mice after skin application of NDMA, indicates that this chemical (or a

metabolite) was distributed to the lungs.

2.6.3 Metabolism

Evidence from in vitro and in vivo studies with rodents indicates that

NDMA is metabolized by hydroxylation of the a-carbon, followed by formation

of formaldehyde, molecular nitrogen and a methylating agent, which is

considered to be the carcinogenic form (Lotlikar et al. 1975; Czygan et al.

1973). Recent evidence suggests that a significant proportion of NDMA is

metabolized via a denitrosation mechanism. The latter mechanism takes place

in rats in vivo, as indicated by the urinary excretion of labelled

methylamine after i.v. administration of 14C-NDMA (Keefer et al. 1987), and

in human liver microsomes (Yoo et al. 1988). The metabolism of NDMA is

summarized in Figure 2-3.

Metabolism of NDMA varies among species (Prassana et al. 1985;

Montesano et al. 1982). Age of the animal and route of administration can

also influence the rate of metabolism of NDMA (Phillips et al. 1975). In

addition, at varying doses, different forms of enzymes appear to be

responsible for NDMA metabolism (Kroeger-Koepke and Michejda 1979; Lotlikar

et al. 1978).

2.6.3.1 Inhalation Exposure

No studies were located regarding the metabolism of NDMA following

inhalation exposure of humans or animals.

2.6.3.2 Oral Exposure

No studies were located regarding the metabolism of NDMA following

oral exposure of humans.

Phillips et al. (1975) demonstrated that NDMA is metabolized at a

lower rate when given orally to rats than when administered by parenteral

routes.

51

2. HEALTH EFFECTS

2.6.3.3 Dermal Exposure

No studies were located regarding the metabolism of NDMA following

dermal exposure of humans or animals.

2.6.4 Excretion

Labelled C02 can be detected in the exhaled air 1 hour after i.p.

administration of 14C-NDMA to rats (Phillips et al. 1975). Hemminki (1982)

administered labelled NDMA by intraperitoneal injection to rats and was able

to detect three main radioactive fractions in the urine over a period of 5

days. Fraction I was composed of radioactive aminoacids, fraction II of

allantoin and a metabolite of thiazolidine-4-carboxylic acid, and fraction

III of 7-methylguanine.

2.6.4.1 Inhalation Exposure

Klein and Schmezer (1984) reported that 10-30% of NDMA is excreted by

exhalation after exposing rats to the chemical during 10 minutes by

endotracheal intubation. In beagle dogs, 23% of the administered

radioactive label is exhaled in 30 minutes after a 3 hour inhalation

exposure (Raabe 1986).

2.6.4.2 Oral Exposure

Spiegelhalder et al. (1982) reported that, in a 24 hour period, human

volunteers excreted in the urine between 0.5 and 2.4% of an ingested dose of

12-30 pg of NDMA added to drinking fluids containing ethanol.

Unchanged NDMA was recovered in the urine and feces of rats up to 24

hours after a single oral dose of 50 mg (Magee 1956). Swann et al. (1984)

did not detect labelled NDMA in the urine of rats after oral administration

of 30 μg/Kg of 14C-NDMA in water. Phillips et al. (1975 determined that

after administration of a single oral dose of 5 mg of 14C-NDMA to female

rats the maximum rate of 14C02 production was 12.4% of the dose/hour, and

that 48% of the dose could be recovered as 14C02 in the exhaled air in 7

hours and 5.7% as 14C (total label) in a 24 hour urine sample.

2.6.4.3 Dermal Exposure

No studies were located regarding the excretion of NDMA following

dermal exposure of humans or animals.

2.7 INTERACTIONS WITH OTHER CHEMICALS

NDMA is normally formed by bacteria in the human stomach and small

intestine, but not in the large intestine (Archer et al 1982; Spiegelhalder

and Preussmann 1985; Zeisel et al. 1988). Also, rats and guinea pigs have
52

2. HEALTH EFFECTS

been shown to make NDMA in their stomachs (Hashimoto et al. 1976; Omori et

al. 1979). Small amounts of NDMA are formed in the saliva of humans;

concentrations can vary from 4 to 10 pg/mL depending on pH and type of food

in the mouth (Rao et al. 1982). NDMA formation in the saliva can be

increased by chemicals such as chlorogenic acid, which is found in coffee,

and decreased by a number of synthetic additives, as well as caffeic acid,

tannic acid and ascorbic acid, which are found in coffee, tea, and citrus

fruits, respectively.

Consumption of alcohol has been shown to have complicated effects on

the toxicity of NDMA. Rats that received alcohol (ethanol or isopropanol)

by gavage for 2 days before receiving NDMA had more liver damage with the

alcohol than without it (Lorr et al. 1984; Maling et al. 1975). Increased

levels of plasma glutamic pyruvate transaminase were monitored and used as a

sign of liver damage. Another study showed that 4 weeks of ethanol

pretreatment in rats worsened the effects on DNA repair that occurred

following DNA alkylation induced by NDMA (Mufti et al. 1988). There is at

least one other study in rats, however, that showed that 23 days of

pretreatment with ethanol decreased the hepatotoxicity of NDMA (Gellert et

al. 1980).

Other substances to which people are exposed have been shown to alter

the toxic effects of NDMA in rats. Vitamin E and calcium channel blocking

agents have been shown to decrease the hepatotoxicity associated with NDMA

(Landon et al. 1986; Skaare and Nafstad 1978). Selenium increased the toxic

effect of NDMA on the liver (Skaare and Nafstad 1978) and cadmium increased

the carcinogenic effect of NDMA in the kidney (Wade et al. 1987). NDMA

induced higher incidences of stomach cancer in rats fed diets low in zinc

than in those fed normal diets (Ng et al. 1984). Rats fed diets low in

copper developed more kidney tumors from NDMA than rats fed normal diets

(Carlton and Price 1973). In contrast, rats given NDMA and cupric acetate

had fewer tumors than rats given NDMA (Yamane et al. 1984). Although these

data indicate that simultaneous administration of other chemicals may

augment NDMA toxicity in animals, it not clear how these simultaneous

exposures may occur in humans.

2.8 POPUIATIONS THAT ARE UNUSUALTaY SUSCEPTIBLE

People with chronic renal failure produce more NDMA in their small

intestines due to increased levels of bacterial growth than normal people do

(Lele et al. 1983). This increase in NDMA can be blocked by injections of

ascorbic acid or antibiotics, but is potentiated by alcohol (Lele et al.

1987). People who consume alcohol may be unusually susceptible to NDMA for

reasons discussed in Section 2.7.

2.9 ADEQUACY OF THE DATABASE

Section 104 (i) (5) of CERCLA, directs the Administrator of ATSDR (in

consultation with the Administrator of EPA and agencies and programs of the
53

2. HEALTH EFFECTS

Public Health Service) to assess whether adequate information on the health

effects of NDMA is available. Where adequate information is not available,

ATSDR, in cooperation with the National Toxicology Program (NTP), is

required to assure the initiation of a program of research designed to

determine these health effects (and techniques for developing methods to

determine such health effects). The following discussion highlights the

availability, or absence, of exposure and toxicity information applicable to

human health assessment. A statement of the relevance of identified data

needs is also included. In a separate effort, ATSDR, in collaboration with

NTP and EPA, will prioritize data needs across chemicals that have been

profiled.

2.9.1 Existing Information on Health Effects of

N-Nitrosodimethylamine

Information regarding health effects of NDMA in humans is limited to

case reports of fatalities due to hepatotoxicity following ingestion or

inhalation. Health effects of NDMA in animals have been investigated in

numerous oral studies and several inhalation and dermal studies. As

indicated in Figure 2-4, animal oral data are available for lethality,

systemic toxicity, immunological effects, neurological effects,

developmental effects, reproductive effects, genotoxic effects and cancer.

These data indicate that hepatotoxicity and cancer are the most prominent

NDMA-related effects.

2.9.2 Data Needs

Single Dose Exposure. Information on lethality in rats following

single oral doses, including two LD50 values, are available. Information on

hepatic effects in rats due to single oral exposures are also available.

Additional single dose oral studies with rats would provide more information

on thresholds for lethality and hepatotoxicity, and on nonhepatic effects.

Studies on species other than the rat would provide data on interspecies

differences. Single-exposure inhalation experiments provide limited

information on lethality in rats, mice and dogs, and dermal/ocular effects

in rats; additional studies could corroborate these data as well as provide

NOAELs. Single application dermal studies would provide information on

lethality and skin and eye irritation.

Repeated Dose Exposure. Numerous repeated dose studies of

intermediate duration have been conducted with rats, mice and other species.

These studies provide extensive information on doses and treatment schedules

that are lethal and hepatotoxic but do not adequately identify thresholds

for these effects, particularly in species that may be more sensitive (e.g.,

mink). Additional repeated dose oral studies designed to examine tissues

other than the liver could provide useful information on nonhepatic systemic

effects of NDMA. Oral studies conducted over periods longer than 20-30 weeks

may not be necessary as sufficient evidence indicates that cancer will be

the predominant effect. Repeated exposure inhalation studies could provide

55

2. HEALTH EFFECTS

information on concentrations associated with lethality and systemic

effects.

Chronic Exposure and Carcinogenicity. Chronic oral and inhalation

studies of NDMA have been conducted with rats and mice. These studies

indicate that the predomin&nt effect of chronic exposure to NDMA is cancer.

As low doses of NDMA have been tested in chronic oral studies and it is

established that intermediate duration exposure to NDMA is sufficient to

induce cancer, additional chronic studies may not be needed.

Genotoxicity. The genotoxic potential of NDMA is established

unequivocally. Only several studies, however, evaluated genotoxic effects in

animals following oral or inhalation exposure to NDMA, and only several in

vitro studies evaluated human cells. Additional studies, particularly assays

with human cells and assays providing information on the potential for

heritable mutations, would add to the data base on genotoxicity.

Reproductive Toxicity. Oral exposure to NDMA for 75 days prior to

mating had no significant effect on time-to-conception in mice. Other

reproductive indices or species have not been evaluated. Histological

examinations of reproductive organs of animals exposed in subchronic and

chronic studies would provide relevant data. Multigenerational or

continuous breeding studies would provide further information regarding

reproductive effects of NDMA in animals, which may be related to possible

reproductive effects in human.

Developmental Toxicity. Evidence indicates that NDMA is fetotoxic to

rats and mice, but NOAELs have not been defined. Well-conducted

developmental studies using several exposure levels and environmentally

relevant routes of exposure could provide the dose-response information

necessary to determine the threshold for fetotoxicity and to determine the

possible relevance and risk for humans. Additional studies also could

determine if NDMA is a transplacental carcinogen.

Immunotoxicity. Information regarding immunological effects of NDMA in

humans is not available. Immunosuppression by NDMA has been demonstrated in

a number of intraperitoneal injection studies, but not in an oral study,

with mice. Specific immunotoxicity tests or a battery of immunotoxicity

tests in which NDMA is administered by the oral route would provide a better

assessment of possible immunotoxic effects. Sensitization tests in animals

could provide information on whether an allergic response to NDMA is likely

in humans. Additional studies also could determine if NDMA is a

transplacental carcinogen.

Neurotoxicity. Dogs that were orally treated with NDMA reportedly

experienced central nervous system depression, but it is likely that this

effect is a consequence of liver damage rather than direct neurotoxicity.

Additional information pertaining to neurotoxicity was not found.
56

2. HEALTH EFFECTS

Neurotoxicity tests in animals exposed to NDMA could provide additional

information on possible neurotoxic effects.

Epidemiological and Human Dosimetry Studies. The only information

available concerning effects of NDMA in humans comes from cases of acute

poisoning and subsequent death. In these cases, hemorrhagic and necrotic

alterations and cirrhosis of the liver were observed. On the other hand,

effects in animals have been well documented (Section 2.2). Attempts have

been made to measure occupational exposure to NDMA, in particular in the

rubber industry. Unfortunately these attempts have failed because NDMA is

metabolized almost completely to CO2 and water. Excretion rates for NDMA

measured in experimental animals are in the order of 0.02% of the ingested

dose (Spiegelhalder 1984). Although unchanged NDMA is unlikely to be

detected in the urine, it may be possible to measure urinary excretion of

nonspecific DNA adducts (e.g., 7-methylguanine). As stated by Spiegelhalder

(1984), limited information is available on airborne exposures of individual

workers for the following reasons: 1) usually workers are exposed to a

variety of chemicals and there is cross-contamination between jobs, 2)

transfers from job to job involve different exposures, 3) increases in

cancer incidences most likely result from exposures that occurred in the

past, when no exposure data were available, and 4) no comprehensive study

has been conducted so far. Epidemiology studies of individuals who live in

areas where NDMA has been detected are necessary to obtain information on

whether NDMA induces effects in humans similar to those seen in animals.

Biomarkers of Disease. Since acute NDMA poisoning in humans caused

severe liver disease, sensitive clinical biochemistry liver function tests

might detect early hepatic damage from toxic exposure to NDMA. Recently,

Wild et al. (1987), using a radioimmunoassay, were able to detect elevated

levels of the promutagenic lesion O6

 -methyldeoxyguanosine in DNA of

esophageal cells from individuals with high incidence of esophageal and

stomach cancer. These individuals were found to consume foods with a

relatively high content of nitrosamines.

Disease Registries. The only known health effects of NDMA on humans are

those obtained from acute poisoning cases, in which postmortem examination

revealed severe liver damage. If disease states attributed to exposure to

NDMA could be identified by epidemiological studies, the number of

individuals affected, the exposure levels involved, and the factors

associated with identifying the disease in a given population, such as, the

vicinity to hazardous waste sites or industrial plants, could be determined.

Bioavailability from Environmental Media. No studies were located

regarding the bioavailability of NDMA from environmental media. Since NDMA

has been detected in ambient air, water and soil (ppb levels), it is

important to determine if NDMA can be absorbed by humans from environmental

samples. It must be noted that NDMA has been found in trace amounts in some

foods and beverages and that endogenous formation of NDMA has been found to

occur from the nitrosation of amines in the gastrointestinal tract. An
57

2. HEALTH EFFECTS

understanding of the bioavailability of NDMA from environmental media may be

obtained by studying the biological fluids of individuals exposed in the

workplace or through the ingestion of NDMA-containing foods and beverages.

The limited information available regarding absorption parameters of NDMA

in experimental animals indicates that NDMA is rapidly absorbed from the

gastrointestinal tract; therefore, one can assume that if water or soil

contaminated with NDMA are ingested, NDMA will be readily absorbed.

Food Chain Bioaccumulation. No studies were available concerning food

chain bioaccumulation of NDMA from environmental sources. NDMA has been

detected in samples of cooked fish and meat. However, occurrence of NDMA in

these samples is not the result of bioaccumulation but is the result of

formation during preservation and/or cooking (Scanlan 1983). Estimation

techniques have been used to determine that NDMA would not bioaccumulate in

lipids of fish (see Section 5.3.1). Based on this limited amount of

information, it is speculated that human exposure to NDMA through diet is

not the result of food chain bioaccumulation. Monitoring for the

accumulation of NDMA in organisms from several trophic levels could be used

to support this conclusion.

Absorption, Distribution, Metabolism, Excretion. Examination of

Section 2.6 clearly indicates that oral administration of NDMA has been the

preferred route for studying its absorption, distribution, metabolism and

excretion. This is not surprising since oral administration is easier to

monitor when compared to other routes. The oral route seems to be the most

pertinent to study since humans are most likely to be exposed to

nitrosamines orally. Toxicokinetic data with regard to dermal and inhalation

exposure of NDMA are clearly lacking. Furthermore, dermal and inhalation

exposures may lead to different metabolic pathways and patterns of

distribution and excretion, which could account for differences in the

degree of toxicity exhibited by different routes of exposure. The metabolism

of NDMA in isolated microsomal preparations seems to be well understood, but

studies with cultured human cells could provide additional useful

information. However, exploration of the denitrosation mechanism as an

alternative to a-hydroxylation requires more attention. Determination of the

urinary excretion of NDMA in control human volunteers and in individuals

known to consume foods with high contents of nitrosamines could provide

information concerning absorption and excretion of the xenobiotic.

Comparative Toxicokinetics. No studies were located regarding

comparative toxicokinetics of NDMA in vivo. In vivo studies are available

indicating differences in hepatic 06

 -methylguanine repair activity among

rodent species (O'Connor et al. 1982). A report by Prasanna et al. (1985)

indicates that the in vitro metabolism of NDMA by liver microsomes from

hamsters, rats and chickens is qualitatively similar, but with different

rates. Montesano et al. (1982) showed that liver slices from humans have a

metabolic capacity to activate NDMA similar to that found in rats and

slightly lower than that found in liver slices from hamsters. Differences

among species in the toxic responses to a chemical can be attributed to
58

2. HEALTH EFFECTS

differences in the toxicokinetic parameters. This seems to be particularly

true for N-nitrosamines in general (Lijinsky 1987). The fact that a number

of factors (animal species, route of exposure, dosing schedule) appear to

determine the organ-specificity and the severity of the effect of NDMA

indicates that caution must be exercised when assuming possible effects in

humans. Although little information is available regarding the

toxicokinetics of NDMA in humans, analysis of NDMA in the urine of

individuals accidentally exposed to the chemical or of individuals consuming

foods with a relatively high content of NDMA could provide quantitative

information on absorption and excretion.

2.9.3 On-going Studies

Two studies regarding the immunotoxicity of NDMA are known to be

ongoing (Federal Research In Progress, 1988). One is investigating the

immunosuppressive activity of subchronic and chronic administration of NDMA,

specifically the in vitro antibody response of NDMA treated spleen cell

suspensions to a number of mutagens. This research is being performed by

Holsapple at Virginia Commonwealth University. A second study, performed by

Schook at the University of Illinois, is attempting to identify molecular

mechanisms for the immunosuppressive effects of NDMA.

In research being conducted by Anderson at the Division of Cancer

Etiology, National Cancer Institute, NDMA is being examined for its ability

to cause neurogenic tumors in mice by transplacental exposure.

In studies sponsored by NIEHS, Faustman at the Univerity of Washington

is evaluating NDMA and other related N-nitroso compounds for their in vitro

developmental toxicity (Faustman 1989).

A number of ongoing studies are investigating the metabolism of NDMA

(Federal Research in Progress, 1988). These include N-nitroso compound

detoxification by Jensen at Temple University, Philadelphia, PA, formation

and metabolism of nitrosamines in pigs by Magee at Temple University,

metabolism and genotoxicity of nitrosamines in rats by Rogan at the

University of Nebraska, Omaha, NE, and enzymology of nitrosamine metabolism

in rats, mice and rabbits in a NCI-sponsored study by Yang at the University

of Medicine and Dentistry, Newark, NJ. Other studies sponsored by NCI are

being conducted to find means of shifting the balance of the metabolic

pathway towards increasing inactivation and characterizing the possible role

of α-nitrosamino radicals in the metabolism of NDMA (written communication,

Keefer 1989).
59

3. CHEMICAL AND PHYSICAL INFORMATION

3.1 CHEMICAL IDENITY

Data pertaining to the chemical identity of NDMA are listed in Table

3-1.

3.2 PHYSICAL AND CHEMICAL PROPERTIES

The physical and chemical properties of NDMA are presented in Table

3-2.



63

4. PRODUCTION, IMPORT, USE, AND DISPOSAL

4.1 PRODUCTION

NDMA is not produced for commercial use in the United States (HSDB

1988). The public portion of the U.S. EPA TSCA Production File indicates

that during 1977, the Ames Laboratories in Milford, CT and Columbia Organics

in Columbia, SC both prepared small research quantities of this chemical.

Eastman-Kodak in Rochester, NY and Teledyne McCormick Selph, an importer,

supplied no NDMA during 1977, although both had the capability to

produce/import this compound and had done so in the past (EPA 1977). Small

research quantities of this chemical presently are available from Sigma

Chemical Co. and Aldrich Chemical Co. NDMA can be prepared by reaction of

nitrous acid with dimethylamine or by addition of acetic acid and sodium

4.2 IMPORT

Data pertaining to the import of NDMA into the U.S. were not located in

the available literature.

4.3 USE

NDMA is prepared in laboratory-scale quantities solely for use as a

research chemical (HSDB 1988). NDMA was formerly used (prior to April 1,

1976) as an intermediate in the production of l,l-dimethylhydrazine, a

storable liquid rocket fuel, which was believed to have contained up to 0.1%

NDMA as an impurity (IARC 1978). NDMA has also been used or has been

proposed for use as an antioxidant, additive for lubricants, and as a

softener for copolymers (Windholz 1983). NDMA has also been used as a

solvent and rubber accelerator (Hawley 1981).

4.4 DISPOSAL

Combustion in an incinerator equipped with an afterburner and NOx

scrubber is the recommended method for disposing NDMA. Liquid wastes

should be neutralized, if necessary, filtered to remove solids, and then put

into closed polyethylene containers for transport. All equipment should be

thoroughly rinsed with solvent, which should be added to the liquid waste

for incineration. Great care should be practiced to insure that there is no

contamination on the outside of the solvent container. If possible, solid

waste should also be incinerated. If this is not possible, the nitrosamine

should be extracted from the waste and the extract should be handled as a

liquid waste. Any rags, papers or other materials which are contaminated

during the disposal process should be incinerated. Contaminated solid

materials should be enclosed in sealed plastic bags that are labeled cancer

suspect agent, with the name and amount of carcinogen. Bags should be

stored in well-ventilated areas until they are incinerated (HSDB 1988).

Nitrosamine residues generated in laboratory research or accidental spills
64

4. PRODUCTION, IMPORT, USE, AND DISPOSAL

in research laboratories should be diluted to a concentration of less than

10 μg/L and then reduced to innocuous amines, ammonia, or alcohols by

aluminum-nickel alloy powder and aqueous alkali. This method of disposal is

applicable to a variety of media (water, mineral oil, olive oil,

dimethylsulfoxide, solutions of agar gel), but is not recommended for use in

solutions of acetone or dichloromethane because reactions are slow and

incomplete. After the reduced reaction mixture is filtered, the liquid can

be disposed of by pouring it over a sufficient amount of absorbent material

to convert it to a solid waste for incineration. The filtercake is

discarded with non-burnable solid wastes (HSDB 1988). Other methods of

destruction of NDMA in laboratory wastes (e.g., using hydrobromic acid or

potassium permanganate/sulfuric acid) are described by IARC (1982).

4.5 ADEQUACY OF THE DATA BASE

Section 104 (i) (5) of CERCLA, directs the Administrator of ATSDR (in

consultation with the Administrator of EPA and agencies and programs of the

Public Health Service) to assess whether adequate information on the health

effects of NDMA is available. Where adequate information is not available,

ATSDR, in cooperation with the National Toxicology Program (NTP), is

required to assure the initiation of a program of research designed to

determine these health effects (and techniques for developing methods to

determine such health effects). The following discussion highlights the

availability, or absence, of exposure and toxicity information applicable to

human health assessment. A statement of the relevance of identified data

needs is also included. In a separate effort, ATSDR, in collaboration with

NTP and EPA, will prioritize data needs across chemicals that have been

profiled.

4.5.1 Data Needs

Production, Use, Release, and Disposal. Uses, methods of synthesis,

and methods of disposal for NDMA are described in the literature and there

does not appear to be a need for further information on these topics. Lack

of information pertaining to the import of this compound is not surprising

since this compound has no commercial applications. Data regarding the

amount of NDMA released to air, water, and soil would be useful in order to

establish potential sources of exposure and levels of exposure from

environmental media. In particular, information releases from hazardous

waste landfills and industries in which this compound is inadvertently

formed may help determine whether people living in the vicinity of these

sites are exposed to elevated levels of this compound. According to the

Emergency Planning and Community Right to Know Act of 1986 (EPCRTKA),

(§313), (Pub. L. 99-499, Title III, §313), industries are required to submit

release information to the EPA. The Toxic Release Inventory (TRI), which

contains release information for 1987, became available in May of 1989.

This database will be updated yearly and should provide a more reliable

estimate of industrial production and emission.
65

5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

NDMA is not an industrially or commercially important chemical;

nevertheless, it can be released into the environment from a wide variety of

manmade sources. This is due to the inadvertent formation of NDMA in

industrial situations when alkylamines, mainly dimethylamine and

trimethylamine, come in contact and react with nitrogen oxides, nitrous

acid, or nitrite salts, or when trans-nitrosation via nitro or nitroso

compounds occurs. Thus, potential exists for release into the environment

from industries such as tanneries, pesticide manufacturing plants, rubber

and tire manufacturers, alkylamine manufacture/use sites, fish processing

industries, foundries and dye manufacturers. At this time, NDMA has been

found in at least 1 out of 1177 hazardous waste sites on the National

Priorities List (NPL) in the United States (VIEW Database 1989).

Nitrosation reaction may also result in the formation of NDMA in the

environment. In air, NDMA may form as a product of the nighttime reaction

of dimethylamine with NOx. In water and soil, NDMA forms by the reaction of

widely-occurring primary, secondary or tertiary amines in the presence of

nitrite.

In the ambient atmosphere, NDMA should be rapidly degraded upon

exposure to sunlight. The half-life for direct photolysis of NDMA vapor is

on the order of 5 to 30 minutes. In surface water exposed to sunlight, NDMA

would also be subject to photolysis. On soil surfaces, NDMA would be

subject to removal by photolysis and volatilization. The volatilization

half-life of NDMA from soil surfaces under field conditions has been found

to be 1 to 2 hours. In subsurface soil and in water beyond the penetration

of sunlight, NDMA would be susceptible to slow microbial decomposition under

both aerobic and anaerobic conditions. In aerobic subsurface soil, the

half-life of NDMA has been found to be about 50 to 55 days. Degradation has

been found to proceed slightly faster under aerobic conditions than under

anaerobic conditions.

NDMA has been detected in ambient air, water and soil; however,

monitoring data are rather scant. Low levels of NDMA (measurable in terms

of ppb) are commonly found in the air of car interiors, food, malt beverages

(beer, whiskey), toiletry and cosmetic products, rubber baby bottle nipples

and pacifiers, tobacco products and tobacco smoke, pesticides used in

agriculture, hospitals, and homes, and sewage sludge.

The general population is exposed to NDMA from a variety of different

sources. Primary sources of exposure include: chewing tobacco, tobacco

smoke, foods [beer, liquor, cured meats (particularly bacon), fish, cheeses,

and other food items], cosmetics and toiletry articles, interior air of

cars, various household commodities such as detergents and home-and-garden

pesticides, and formation in the upper gastrointestinal tract during

digestion of secondary amine-containing foods. Infants may also be exposed
66

5. POTENTIAL FOR HUMAN EXPOSURE

to NDMA from the use of rubber baby bottle nipples and pacifiers which may

contain very low amounts of NDMA, from ingestion of contaminated infant

formula, and from breast milk from some nursing mothers. Very low levels of

NDMA have been found in breast milk. Occupational settings in which there

is potential for exposure to NDMA include, but are not limited to: leather

tanneries, rubber and tire industries, rocket fuel industries, dye

manufacturers, soap, detergent and surfactant industries, foundries

(coremaking), fish-processing industries (fish-meal production), pesticide

manufacturers, warehouse and sale rooms (especially for rubber products),

and research laboratories where NDMA is synthesized/studied.

5.2 RELEASES TO THE ENVIRONMENT

5.2.1 Air

NDMA may occasionally be emitted into the atmosphere from sites of

manufacture/use of dimethylamine and other sites at which NDMA is

inadvertently formed, i.e. tanneries, pesticide manufacturing plants, rubber

and tire industries, etc. NDMA may also form in nighttime air as the result

of the atmospheric reaction of dimethylamine with NOx (Cohen and Bachman

1978, Fine et al. 1976a, Fine et al. 1976b, Hanst et al. 1977).

5.2.2 Water

NDMA may be released in waste streams from facilities at which NDMA was

inadvertently formed during manufacturing processes. This would include

such facilities as amine manufacturing plants, tanneries, rubber and tire

industries, fish processing industries, foundries, rocket fuel industries,

dye manufacturers, soap, detergent, and surfactant industries, and pesticide

manufacturers (Cohen and Bachman 1978). In addition to industrial sources,

NDMA may form in aqueous systems, sewage and soil as the result of either

biological, chemical or photochemical processes. Biological formation

occurs via the reaction of a secondary or tertiary amine with nitrite. The

nitrite can arise in the environment from the microbial transformation of

ammonia or nitrate or through manmade production. Chemical formation of

nitrosamines occurs optimally under acidic conditions and may occur from the

reaction of primary, secondary or tertiary amines with nitrite (Ayanaba and

Alexander 1974; Mills and Alexander 1976). Formation of NDMA by

photochemical transformation of dimethylamine in the presence of nitrite has

been found to occur more readily under alkaline conditions than under acidic

or neutral conditions (Ohta et al. 1982). Nitrosamine precursors are

widespread throughout the environment, occurring in plants, fish, algae,

urine, and feces and are formed in the environment as pesticide degradation

products (Ayanaba and Alexander 1974, Greene et al. 1981, Neurath et al.

1977, Windholz 1983). The Contract Laboratory Program statistical data base

reports that NDMA has been detected in groundwater samples at one out of

1177 hazardous waste site on the National Priorities List (NPL). This site

is Martin Marietta (Denver Aerospace) in Waterton, CO (VIEW Database 1989):
67

5. POTENTIAL FOR HUMAN EXPOSURE

No data are available regarding contamination of drinking water,

irrigation water, sewers, or storm drains in the vicinity of NPL sites.

5.2.3 Soil

NDMA may be released into the environment as the result of land

application of sewage sludge containing this compound or as the result of

land application of certain pesticides contaminated with this compound.

NDMA may also form in soils under conditions which favor nitrosation of

nitrosamine precursors (Mills and Alexander 1976, Pancholy 1978). There is

rio data pertaining to the detection of NDMA in soil samples collected at or

in the vicinity of NPL sites.

5.3 ENVIRONMENTAL FATE

5.3.1 Transport and Partitioning

Organic compounds in the atmosphere having vapor pressures greater than

10-4 mm Hg are expected to exist almost entirely in the vapor phase

(Eisenreich et al. 1981). The esgimated vapor pressure of NDMA [2.7 mm Hg

at 20°C (see Table 3-2)] indicates that this compound should not partition

from the vapor phase to particulates in the atmosphere.

Using linear regression equations based on log Kow data [log Kow =

-0.57 (see Table 3-2)], a bioconcentration factor of 0.2 and a soil

adsorption coefficient (Koc) of 12 have been estimated for NDMA (Bysshe

1982, Hansch and Leo 1985, Lyman 1982). These values, as well as the

complete water solubility of NDMA, indicate that bioaccumulation in aquatic

organisms and adsorption to suspended solids and sediments in water would

not be important environmental fate processes. The low value of the Henry's

Law Constant for NDMA [2.63x10-7 atm-m3

/mol at 20°C (see Table 3-2)]

suggests that volatilization would be a relatively insignificant fate

process in water (Thomas 1982).

NDMA is expected to be highly mobile in soil and it has the potential

to leach into groundwater supplies (Dean-Raymond and Alexander 1976, Greene

et al. 1981, Swann et al. 1983). If NDMA were released to soil surfaces, as

might be the case during application of contaminated pesticides, a

substantial proportion of the nitrosamine would volatilize. The

volatilization half-life from soil surfaces under field conditions is

estimated to be on the order of l-2 hours (Oliver 1979). If NDMA were

incorporated into subsurface soil, far less of the nitrosamine would enter

the atmosphere by volatilization and the rate of volatilization would be

greatly reduced. Under these circumstances volatilization would be of minor

importance (Oliver 1979).
68

5. POTENTIAL FOR HUMAN EXPOSURE

5.3.2 Transformation and Degradation

5.3.2.1 Air

In the atmosphere, NDMA vapor would rapidly degrade by direct

photolysis to form dimethylnitramine. Based on experimental data, the

photolytic half-life of NDMA vapor exposed to sunlight has been determined

to be about 5 to 30 minutes (Hanst et al. 1977, Tuazon et al. 1984).

Reaction of NDMA with photochemically-generated hydroxyl radicals or ozone

molecules in the atmosphere would be too slow to be environmentally .

significant (Atkinson and Carter 1984, Tuazon et al. 1984).

5.3.2.2 Water

Limited available data suggest that NDMA would be subject to slow

photolysis in natural waters exposed to sunlight (Polo and Chow 1976;

Callahan et al. 1979). In unlit waters, it appears that NDMA would be

rather persistent, eventually degrading as the result of microbial

transformation (Kaplan and Kaplan 1985, Kobayashi and Tchan 1978, Tate and

Alexander 1975). There is evidence which suggests that formaldehyde and

methylamine may form as biodegradation products of NDMA (Kaplan and Kaplan

1985). Insufficient data are available to predict the rate at which NDMA

would degrade in water. NDMA is not expected to chemically react under the

conditions found in natural waters (Callahan et al. 1979, O.liver et al.

1979).

5.3.2.3 Soil

It appears that microbial degradation would be an important removal

process for NDMA in subsurface soil. Oliver et al. (1979) amended

Metapeake loam with 10 ppm NDMA at 23°C and observed a half-life of 50 days

(Oliver et al. 1979). Loss of NDMA was attributed to volatilization and

biodegradation. Tate and Alexander (1975) amended silt loam with 22.5 ppm

NDMA at 30°C and observed a lag of approximately 30 days before slow

disappearance from soil commenced; 50% loss occurred after about 55 days

incubation and 60% loss occurred after about 70 days incubation. As part of

the same study, 40% loss was observed in 2 days in soil amended with 50 ppm

NDMA and 44% loss was observed in 5 days in soil amended with 250 ppm NDMA.

These initial losses were followed by very little or no loss over the next 3

weeks. Initial, rapid loss of NDMA was attributed to volatilization and

slow, gradual loss of NDMA was attributed to biodegradation. Mallik and

Tesfai (1981) incubated NDMA at 4, 25 and 37°C and found that at all three

temperatures, about 20-30% of added NDMA disappeared in the first 20 days of

incubation, but little loss was noted thereafter; even after 30 days of

incubation, over 50% of the NDMA was retained. The rate of disappearance of

NDMA was found to be slightly higher in sandy loam soil than in either clay

or silt loam soil. The rate of loss was also found to be slightly higher in

aerobic soil at field capacity compared to super saturated (anaerobic) soil.

After a 30-day incubation period, 60% of added NDMA remained in soil at
69

5. POTENTIAL FOR HUMAN EXPOSURE

field capacity and 70% of added NDMA remained in super saturated soil.

Available data on the degradation of NDMA in water and air indicate that

photolysis may be an important removal process on soil surfaces.

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

5.4.1 Air

When it was used as a rocket fuel intermediate, NDMA was identified in

ambient air on-site and in the vicinity of factories which were

manufacturing rocket fuel (Fine et al. 1977b; Gordon 1978). At a plant in

Baltimore, MD, which was manufacturing unsymmetrical dimethylh drazine

rocket fuel, the average concentration on-site was 11,600 ng/m3 , and in

neighboring residential communities it was 1,070 ng/m3 , with levels ranging

between 30 to 100 ng/m3

 in the downtown area (Fine et al. 1977b). As a

result of these findings, the use of NDMA was discontinued at this plant

(Shapley 1976). During December 1975, NDMA was found in air samples

collected in Belle, WV near a factory which was manufacturing dimethylamine.

The highest level found (980 ng/m3

) was collected during a temporary weather

inversion (Fine et al. 1976b). NDMA has also been measured in ambient air

in urban areas with no known point sources of nitrosamines: Baltimore, MD

several miles upwind of the rocket fuel plant (0.02-0.1 μg/m3

); the Cross

Bronx Expressway in New York City (0.8 μg/m3

); and Philadelphia, PA (0.025

ppb) (Fine et al. 1976b, Shapley 1976).

Occurrence of volatile nitrosamines in air has been associated with

tire and rubber products, leather tanneries, and automotive upholstery, and,

as a result, measurable levels of the nitrosamines have been found in

certain confined areas, e.g. automobile interiors. Concentrations of NDMA

in interior air of automobiles have been found to vary widely due to

differences in age of the car, design and decor. Levels of NDMA in interior

air of new cars were found to range from <0.02 to 0.83 μg/m3

 (Dropkin 1985,

Rounbehler et al. 1980).

5.4.2 Water

Data from the EPA STORET Water Quality data base indicate that NDMA is

not a common contaminant of surface waters in the United States (EPA 1988b).

During the time when NDMA was being used as a chemical intermediate at a

rocket fuel manufacturing plant in Baltimore, MD, concentrations up to 940

ng/L were found in adjacent surface waters. Mud puddles adjacent to the

facility contained 0.20-9.0 mg/kg (moist basis) of NDMA (Fine et al. 1977b).

Information found in STORET also reveals that NDMA is infrequently found in

groundwater samples. STORET gross analysis data input from 1980 to 1988

indicate that NDMA was positively identified in 0.9% of 2308 groundwater

samples collected in the United States. The average concentration of

positive samples was 12.4 μg/L (EPA,l988b). NDMA also has been detected at

a concentration of 10 μg/L in groundwater samples at one of 1177 hazardous

waste sites on the National Priorities List (NPL). This site is Martin
70

5. POTENTIAL FOR HUMAN EXPOSURE

Marietta (Denver Aerospace) in Waterton, Co (VIEW 1989, VIAR 1987). NDMA

was reportedly found in tap water from Philadelphia, PA at levels of 0.003-

0.006 μg/L (Kimoto et al. 1981). The authors of this study concluded that

NDMA did not form in the resin used to accumulate the nitrosamines, but that

it may have formed from the reaction of low concentrations of nitrite, an

oxidizing agent (possibly chlorine) and secondary amines present in the

water sample. NDMA has been found in deionized laboratory water at levels

ranging from 0.03-0.34 μg/L (Fiddler et al. 1977, Gough et al. 1977). Anion

exchanger resins were identified as the source of NDMA found in the water

samples. There have been reports of NDMA occurring infrequently in

wastewater samples collected from various locations situated throughout the

United States. When present, levels of NDMA are generally in the low μg/L

range (maximum reported concentration 2.7 μg/L) (Cohen and Bachman 1978,

Ellis et al. 1982, EPA 1988b, Fine et al. 1977b).

5.4.3 Soil

NDMA has been found in soil at l-8 μg/kg (dry basis) in Belle and

Charleston, WV, New Jersey and New York City (Fine et al. 1977c). It is

speculated that occurrence of NDMA in soil may have arisen from (a)

absorption of NDMA in air, (b) absorption of dimethylamine from air and its

subsequent N-nitrosation, or (c) from pesticide application.

5.4.4 Other Media

N-Nitrosamines are formed in foods by the reaction of secondary and

tertiary amines with a nitrosating agent, usually nitrous anhydride, which

forms from nitrite in acidic, aqueous solution. NDMA is the most common

volatile amine found in food. Food constituents and the physical make-up of

the food can affect the extent of nitrosamine formation. Ascorbic acid and

sulfur dioxide have been used to inhibit the formation of nitrosamines.

NDMA has been found in some processed foods as a result of direct-fire

drying; it forms from the nitrosation of amines in drying food by oxides of

nitrogen in drying air (Scanlan 1983). Trace levels (usually less than 1

ppb) of NDMA have been found in a variety of foods; however, not all samples

of a particular type of food contain detectable levels of NDMA. Table 5-l

lists the levels of NDMA which have been found in food. NDMA may also occur

in human breast milk. In a study of 51 samples of breast milk collected

from 13 nursing women, NDMA concentrations greater than 0.2 ppb were found

in 23.5% of the samples, and the maximum concentration detected was 1.1 ppb

(Lakritz and Pensabene 1984). During this study, it was determined that

eating a meal containing bacon did not result in increased NDMA levels in

milk, although eating a meal containing bacon and a vegetable high in

nitrate occasionally resulted in higher levels of NDMA in breast milk.

NDMA has been found to occur in a variety of toiletry and cosmetic

products, including shampoos, hair conditioners, color toners, shower gels,

bath cremes and oils, children's shampoos, children's bath and health care

products, and face tonics, cleansers, and masks. In a study of 145

72

5. POTENTIAL FOR HUMAN EXPOSURE

products, 50 samples (34.5%) contained NDMA, with a maximum concentration

of 24 μg/kg occurring in a sample of shampoo (Spiegelhalder and Preussman

1984).

The U.S. Food and Drug Administration (FDA) established an action

level, effective January 1, 1984, of 60 ppb total N-nitrosamines in rubber

nipples as measured by a dichloromethane extraction procedure (Thompson

et al. 1986). This means that the Consumer Product Safety Commission can

take action against any company which introduces baby bottle or pacifier

nipples into interstate commerce containing greater than 60 ppb total

N-nitrosamines. Compliance testing of infant pacifiers entered into

commerce after January 1, 1984 and sold in the U.S. revealed that total

N-nitrosamine levels ranged from not detectable to 36.9 ppb, and that NDMA

levels ranged from not detectable to 3.55 ppb, with infrequent occurrence of

NDMA (Billedeau et al. 1986). This compares well with levels found in

pacifiers entered into commerce prior to January 1, 1984, when total

N-nitrosamine levels as high as 332 ppb and NDMA levels as high as 6.78 ppb

were detected using the same analytical procedure (Billedeau et al. 1986).

It should be noted that several companies have discontinued supplying rubber

nipples since January 1984, because they could not meet the compliance

level.

Most malt beverages, regardless of origin, contain NDMA. This includes

many domestic and foreign beers and most brands of whiskey (Havery et al.

1981, Hotchkiss et al. 1981, Scanlan et al. 1980, Sen and Seaman 198lC). It

is generally accepted that the nitrosamine is formed in malt during the

direct-drying phase of its processing (Fazio and Havery 1982). At one time,

it was estimated that 64% by weight, of the dietary intake of NDMA of the

West German male population could be attributed to the consumption of beer

(Hotchkiss et al. 1981, Spiegelhalder et al. 1979). As a result of these

findings, the U.S. Food and Drug Administration established an action level

of 5 ppb for NDMA in malt beverages sold in the United States (Hotchkiss et

al. 1981). Compliance testing of domestic (United States) and imported

beers by the FDA showed that domestic beers (180 samples) contained NDMA

levels ranging from not detectable to 9 ppb, with the average level being

less than 1 ppb (1% contained greater than 5 ppb), and that imported beers

(80 samples) contained levels ranging from not detectable to 13 ppb, with an

average level of 1 ppb (5% contained greater than 5 ppb) (Havery et al.

1981). These results compared favorably with levels found during a market

survey carried out prior to establishment of the action level, when 81% of

domestic beers contained greater than or equal to 1 ppb and 17% contained

greater than 5 ppb (Hotchkiss et al. 1981). Compliance survey data indicate

that levels of NDMA in scotch whiskey (44 samples) ranged from not

detectable to 2 ppb, with an average of less than 1 ppb (Havery et al.

1981).

NDMA is commonly found in commercially-available tobacco products in

the United States. Results of one study showed that chewing tobaccos

purchased in the United States contained NDMA at levels ranging from <0.2 to
73

5. POTENTIAL FOR HUMAN EXPOSURE

85.1 ppb (Brunnemann et al. 1985). NDMA also occurs in mainstream and

sidestream smoke from cigarettes and other tobacco products, with higher

levels occurring in sidestream smoke than in mainstream smoke (Brunnemann

et al. 1983, Chamberlain and Arrendale 1982, McCormick et al. 1973).

Sidestream smoke from commercially-available tobacco products purchased in

the United States were found to contain NDMA at the following levels:

nonfiltered cigarette, 680 rig/cigarette; filtered cigarette, 736

rig/cigarette; and small cigar, 1700 rig/cigarette. The ratio of NDMA in

sidestream smoke to NDMA in mainstream smoke in the non-filtered cigarette,

filtered cigarette and small cigar was found to be 52:1, 139:1, and 41:1,

respectively (Hoffman et al. 1987).

NDMA has been found to occur in various technical and commercial

pesticides used in agriculture, hospitals and homes as the result of (a)

formation during the manufacturing process, (b) formation during storage,

and (c) contamination of amines used in the manufacturing process (Bontoyan

et al. 1979). Herbicides in which NDMA has been found include the amine

salt formulations of 2,4-D, dicamba, MCPA, MCPP,and 2,3,6-trichlorobenzoic

acid. Levels ranging from 0.05 to 640 ppm have been detected inthese

herbicides (Bontoyan et al. 1979, Cohen et al. 1978, Hindle et al. 1987,

Ross et al. 1977).

NDMA is a common constituent of municipal sewage sludge (Brewer et al.

1980, Mumma et al. 1984). NDMA was detected in dried sludges from 14 out of

15 cities geographically located throughout the U.S. at levels ranging from

0.6-45 ppb (Mumma et al. 1984). Occurrence of NDMA in sewage sludge appears

to be the result of biological and chemical transformation of alkylamines in

the presence of nitrite (Ayanaba and Alexander 1974, Mills and Alexander

1976, Pancholy 1978).

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

N-Nitrosamine precursors can be found in a large variety of man-made

and natural products. Such products include agricultural chemicals,

tobacco, detergents, rust inhibitors, rubber additives, solvents, drugs,

plastics, leather tanning, textiles, and cosmetics. Considering the

widespread occurrence of these products and the common occurrence of

nitrogen oxides in industry, there is a fairly high likelihood that

N-nitrosamines are found in these products or in industrial setting in which

these products are used and/or produced (Fajen 1980). Occupational settings

in which there is potential for exposure to NDMA include, but are not

limited to: leather tanneries, rubber and tire industries, rocket fuel

industries, dye manufacturers, soap, detergent and surfactant industries,

foundries (core-making), fish-processing industries (fish-meal production),

pesticide manufacturers, and warehouse and sale rooms (especially for rubber

products) (Spiegelhalder 1984). When present in workroom air, NDMA levels

are typically less than 1 ppb (Fajen et al. 1982). Exposure may result from

inhalation or dermal contact. Results of a NIOSH survey carried out between
74

5. POTENTIAL FOR HUMAN EXPOSURE

1981 and 1983 indicate that 747 workers are potentially exposed to NDMA in

occupational settings (NIOSH 1988).

Laboratory workers handling NDMA could potentially be exposed to the

nitrosamine as a result of diffusion through rubber gloves. Walker et al.

(1978) showed that rubber gloves worn in research laboratories do not

provide complete protection from dermal exposure to NDMA, because 11.8% of

the NDMA contained in a dichloromethane solution was found to diffuse

through latex surgical gloves into saline solution, over a period of 20

minutes. Dichloromethane is a common solvent for NDMA.

General population exposure to NDMA results from a number of different

sources, primarily chewing tobacco, tobacco smoke, foods (beer, cured meats,

fish, cheeses, and other food items), cosmetic products, interior air of

cars, and various household commodities. Exposure to NDMA may also result

from its in vivo formation during digestion in the upper gastrointestinal

tract of secondary amine-containing foods or drugs, especially those

containing dimethylamine (Groenen et al. 1980, Magee et al. 1976, Sakai et

al. 1984). Infants may be exposed to NDMA from baby bottle nipples and

pacifiers which may contain small amounts of NDMA, from ingestion of

contaminated infant formulas, and from breast milk from some nursing

mothers. Very low levels of NDMA have been found in breast milk. Based on

older estimates of dietary intake in Germany, the Netherlands, and England

and on recent data pertaining to occurrence of NDMA in various foods in the

U.S., it appears that the average adult dietary intake of NDMA in the U.S.

is less than 1 μg per day (Preussmann 1984). Insufficient data are

available to predict the average daily intake of NDMA from other sources of

exposure.

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURE

It appears that those segments of the general population with

potentially high exposure to NDMA from exogenous sources would include

tobacco smokers and nonsmokers who come in contact with tobacco smoke for

extended periods of time, snuff dippers, people who are occupationally

exposed, and people who consume large quantities of food known to contain

NDMA, beer or whiskey. .

5.7 ADEQUACY OF THE DATABASE

Section 104 (i) (5) of CERCLA, directs the Administrator of ATSDR (in

consultation with the Administrator of EPA and agencies and programs of the

Public Health Service) to assess whether adequate information on the health

effects of NDMA is available. Where adequate information is not available,

ATSDR, in cooperation with the National Toxicology Program (NTP), is

required to assure the initiation of a program of research designed to

determine these health effects (and techniques for developing methods to

determine such health effects). The following discussion highlights the

availability, or absence, of exposure and toxicity information applicable to
75

5. POTENTIAL FOR HUMAN EXPOSURE

human health assessment. A statement of the relevance of identified data

needs is also included. In a separate effort, ATSDR, in collaboration with

NTP and EPA, will prioritize data needs across chemicals that have been

profiled.

5.7.1 Data Needs

Physical and Chemical Properties. Physical and chemical properties

are essential for estimating the partitioning of a chemical among

environmental media. Many physical and chemical properties are available

for NDMA; however, measured values for Koc and Henry's Law Constant at

ambient temperature are not available. Methods for estimating these

properties appear to provide relatively close estimates of Koc and Henry's

Law Constant. Nevertheless, measured values at environmentally significant

temperatures would assist in accurately predicting the fate of this compound

in the environment.

Environmental Fate. Sufficient data are available to develop a general

understanding of the environmental fate of NDMA. Kinetic data regarding

photolysis in water and on soil surfaces, biodegradation in water under

aerobic and anaerobic conditions, and biodegradation in soil under anaerobic

conditions are lacking. Natural water grab sample biodegradation studies

and soil metabolism studies carried out in the dark under aerobic and

anaerobic conditions would be useful in establishing the persistence of NDMA

in the environment. Photolysis studies carried out under simulated

environmental conditions in water and soil would be useful in establishing

the rate of photolytic degradation, the significance of this process as a

removal mechanism, and the products of this reaction in these media.

Exposure Levels in Environmental Media. Limited data suggest that NDMA

may be found in urban air, but recent comprehensive monitoring data

pertaining to the detection of NDMA in ambient air are needed to establish

this fact. Occurrence of NDMA in air has been associated with rubber

products, leather products, and cigarette smoke and measurable levels of

NDMA have been found in car interiors. This information, combined with the

fact that NDMA has been found in ambient air at various urban locations,

suggests that detectable levels of NDMA exist in the interior air of homes,

offices, etc. Studies pertaining to the monitoring of NDMA in indoor air

are needed to confirm this supposition.

Exposure Levels in Humans. Although numerous studies are available

concerning the detection of NDMA in various foods, a market basket study is

needed to provide a reliable estimate of the average daily dietary intake of

NDMA. Available monitoring data on NDMA need to be evaluated, and estimates

of the amount of exposure from each source need to be developed. These data

would be useful in establishing the relative importance of each source of

intake to overall human exposure and for predicting typical levels of

exposure to NDMA.
76

5. POTENTIAL FOR HUMAN EXPOSURE

Exposure Registries. Since NDMA occurs most commonly in occupational

settings as a result of its inadvertent formation, it would be difficult to

develop a reliable estimate of occupational exposure to this compound.

Nevertheless, NIOSH has established a registry for occupational exposure to

NDMA. It would be difficult to develop a registry for environmental

exposure to NDMA since such exposure can occur from a wide variety of

sources and level of exposure can vary markedly depending upon an

individual's lifestyle. There is no registry available for environmental

exposure to this compound.

5.7.2 On-going Studies

There is no indication that there are any studies currently in progress

which are related to the level of NDMA in environmental media, environmental

fate of NDMA, or general population or occupational exposure to NDMA.
77

6. ANALYTICAL METHODS

6.1 BIOLOGICAL MATERIALS

Methods used for the quantification of NDMA in biological samples are

given in Table 6-1. Two problems encountered in the analysis of NDMA are

poor recovery of the compound due to its high volatility and the artifactual

formation of this compound during sample storage and treatment (Fine 1982).

Since nitroso compounds are formed in acid solution, keeping the solution

alkaline during storage and treatment may reduce artifact formation (Kosaka

et al. 1984). Other authors have used ascorbic acid to inhibit in vitro

formation of nitrosamines and have used morpholine to measure the extent of

in vitro nitrosation during storage and handling (Dunn et al. 1986).

The method that has most selectivity for the quantification of this

compound is thermal energy analyzer (TEA). A few investigators have

oxidized this compound with pentafluoroperoxybenzoic acid to achieve higher

sensitivity with electron capture detector (ECD).than with TEA (Kimoto

et al. 1984). However, ECD detectors have less selectivity than TEA and

will require more sample clean up. The confirmation of NDMA in a sample is

usually done by mass spectrometry (MS). Samples containing small amounts of

NDMA cannot be detected by MS in the presence of large background impurities

(as in samples treated for TEA analysis). Photolysis at 366 nm affords an

alternative means for validating the presence of this compound identified by

TEA (Cooper et al. 1987). A method for the analysis of total N-nitroso

compounds in gastric juice is also available (Pignatelli et al, 1987).

6.2 ENVIRONMENTAL SAMPLES

Methods for quantifying NDMA in environmental samples are summarized in

Table 6-2. As with the biological samples, in situ artifact formation must

be avoided in order to get accurate results from the analysis of

environmental samples (Fisher et al. 1977; Fine et al. 1977a). The three

quantification methods that give satisfactory sensitivity for NDMA are

alkali flame ionization detector (in the nitrogen mode) (AFID), Hall

electrolytic conductivity detector (HECD) in the reductive mode and TEA.

The advantages and disadvantages of these detectors have been evaluated

(Rhoades et al. 1980; Usero et al. 1987). Of the three detectors, the TEA

detector has the highest sensitivity and selectivity. Because of its higher

selectivity, the TEA detector cannot be versatile enough for multipollutant

analysis. Mass spectrometric detector can be used not only for confirmation

of the presence of NDMA in a sample, but for quantification as well

(Eichelberger et al, 1983; Webb et al, 1979). When used in combination

with a high resolution GC column, this method has the ability to quantify a

large number of pollutants in a sample. The use of selected ion monitoring

(SIM) may increase the sensitivity by orders of magnitude. The SIM method

does not provide the full mass spectra necessary for the identification of

unexpected compounds, however (Bellar et al. 1979). A method for the



81

6. ANALYTICAL METHODS

analysis of apparent total N-nitroso compounds in beer is also available

(Massey et al. 1987).

6.3 ADEQUACY OF THE DATABASE

Section 104 (i) (5) of CERCIA, directs the Administrator of ATSDR (in

consultation with the Administrator of EPA and agencies and programs of the

Public Health Service) to assess whether adequate information on the health

effects of NDMA is available. Where adequate information is not available,

ATSDR, in cooperation with the National Toxicology Program (NTP), is

required to assure the initiation of a program of research designed to

determine these health effects (and techniques for developing methods to

determine such health effects). The following discussion highlights the

availability, or absence, of exposure and toxicity information applicable to

human health assessment. A statement of the relevance of identified data

needs is also included. In a separate effort, ATSDR, in collaboration with

NTP and EPA, will prioritize data needs across chemicals that have been

profiled.

6.3.1 Data Needs

Methods for Determining Parent Compounds and Metabolites in Biological

Materials. NDMA is equally distributed in the cellular elements of the

blood and in the plasma and serum (Lakritz et al. 1980). Therefore, it is

advantageous to analyze whole blood for the quantification of NDMA.

Because NDMA is metabolized almost quantitatively in humans (Spiegelhalder

1984), determination of this compound in human urine needs an extremely

sensitive technique (Garland et al. 1986). The urinary excretion of NDMA

has been correlated with the concentration of NO2 in air, suggesting that

ambient air may play a role in the exposure of people to nitrosoamines

(Garland et al. 1986). There is a paucity of data on the analytical methods

for the determination of N-nitrosodimethylamine in human urine.

No metabolite of NDMA from human exposure to this compound has yet been

identified (see Subsection 2.6.3). A metabolite identified in laboratory

animal has been discussed in Subsection 2.6.3. The changes in metabolite

concentrations with time in human blood, urine, or other appropriate

biological medium may be useful in estimating its rate of metabolism in

humans. In some instances, a metabolite may be useful in correlating the

exposed doses to the human body burden. Such studies on the levels of

metabolites in human biological matrices are not available for this

compound.

Methods for Biomarkers of Exposure Recently, a radioimmunoassay was

used to detect elevated levels of the promutagenic lesion 06-

methyldeoxyguanosine in DNA cells from individuals with high incidence of

cancer who consumed foods with a high nitrosamine content (Wild et al,

1987). Although no correlation has been established between the DNA-adduct
82

6. ANALYTICAL METHODS

and the level of NDMA in consumed foods, the DNA-adduct has the potential to

be used as a biomarker for exposure to NDMA.

Methods for Determining Parent Compounds and Degradation Products in

Environmental Media. The levels of this compound in environmental media

can be used to indicate exposure of humans to this compound through the

inhalation of air and ingestion of drinking water and foods containing

N-nitrosodimethylamine. If a correlation with human tissue or body fluid

levels were available, the intake levels from different environmental

sources could be used to estimate the body burden of the chemical in humans.

Such studies correlating the levels of this compound in any environmental

medium with the levels in any human tissue or body fluid are not available.

Although the products of biotic and abiotic processes of this compound

in the environment are known, no systematic study is available that measured

the concentrations of its reaction products in the environment. In

instances where the products of an environmental reaction are more toxic

than the parent compound, it is important that the level of the reaction

products in the environment be known. N-nitrosodimethylamine is not likely

to form more toxic products as a result of environmental reactions (see

Subsection 5.3.2). The analytical methods for the determination of the

levels of environmental reaction products of N-nitrosodimethylamine are

available.

6.3.2 On-going Studies

No ongoing studies are in progress for the improvement of the

analytical method for NDMA in biological samples. Studies are currently

conducted by J. Conboy and J. Hotchkiss at Cornell University, Ithaca, NY

and by D. Havery at FDA, Washington, DC, for the development of analytical

methods for this compound in environmental samples.
83

7. REGULATIONS AND ADVISORIES

The International Register of Potentially Toxic Chemicals (IRPTC 1988)

lists regulations imposed by 13 countries for NDMA for occupational

exposure, packing, storing and transport, disposal, and warns of its

probable human carcinogenicity and its high level of toxicity by ingestion

or inhalation.

NDMA is regulated by effluent guidelines under the Clean Water Act for

the following industrial point sources: electroplating, steam electric

power generation, asbestos products manufacturing, timber products

processing, metal finishing, paving and roofing, paint formulating, ink

formulating, and carbon black manufacturing (EPA 1988a).

Additional national and state regulations and guidelines pertinent to

human exposure to NDMA are summarized in Table 7-l.



87

8. REFERENCES

*Abanobi SE, Farber E, Sarma DSR. 1979. Persistence of DNA damage during

development of liver angiosarcoma in rats fed dimethylnitrosamine. Cancer

Res 39:1592-1596.

*Abe S, Sasaki M. 1982. Induction of sister-chromatid exchanges by indirect

mutagens/carcinogens in cultured rat hepatoma and esophageal tumor cells and

in Chinese hamster Don cells co-cultivated with rat cells. Mutat Res 93:409-

418.

*ACGIH (American Conference of Governmental Industrial Hygienists). 1989.

Threshold limit values and biological exposure indices for 1989-1990.

Cincinnati, OH: ACGIH, 32, 46-47.

*Adair GM, Carver JH. 1983. Induction and expression of mutations at

multiple drug-resistance marker loci in Chinese hamster ovary cells.

Environ Mutagen 5:161-175.

*Aleksandrov VA. 1974. [Embryotoxic and transplacental oncogenic action of

symmetrical dialkynitrosamines on the progeny of rats.] Bull Exp Biol Med

78:1308-1310. (Russian)

*Althoff J, Pour P, Grandjean C, et al. 1977. Transplacental effects of

nitrosamines in Syrian hamsters. 3. Dimethyl- and dipropylnitrosamine. Z

Krebsforsch Klin Onkol 90:79-86.

*Amacher DE, Paillet SC. 1982. Hamster hepatocyte-mediated activation of

procarcinogens to mutagens in the L5178Y/TK mutation assay. Mutat Res

106(2):305-316.

*Amacher DE, Paillet SC. 1983. The activation of procarcinogens to mutagens

by cultured rat hepatocytes in the L5178Y/TK mutation assay. Mutat Res

113:77-88.

*Anderson LM, Giner-Sorolla A, Ebeling D, et al. 1978. Effects of

imipramine, nitrite, and dimethylnitrosamine on reproduction in mice, Res

Commun Chem Pathol Pharmacol 19:311-327.

*Anderson TM, Harrington GW, Pylypiw HM Jr, et al. 1986. Tissue levels and

biological effects of N-nitrosodimethylamine in mice during chronic low or

high dose exposure with or without ethanol. Drug Metab Dispos 14:733-739.

_____________________________________

*Denotes studies cited in text
88

8. REFERENCES

Anderson LM, Hagiwara A, Kovatch RM, et al. 1989. Transplacental

initiation of liver, lung, neurogenic, and connective tissue tumors by

N-nitroso compounds in mice. Fund Appl Toxicol 12:604-620.

*Andrae U, Jahnel P, Greim H. 1979. Induction of DNA repair synthesis in

human lymphoblastoid cells by metabolically activated chemicals as shortterm

test for DNA-damaging compounds [Abstract]. Mutat Res 64:125.

*Andrae U, Schwarz LR. 1981. Induction of DNA repair synthesis in isolated

rat hepatocytes by 5-diazouracil and other DNA damaging compounds. Cancer

Lett 13:187-193.

*Arai M, Aoki Y, Nakanishi K, et al. 1979. Long-term experiment of maximal

noncarcinogenic dose of dimethylnitrosamine for carcinogenesis in rats. Gann

70:549-558.

*Araki A, Muramatsu M, Matsushima T. 1984. Comparison of mutagenicities of

N-nitrosamines on Salmonella tvnhimurium TAlOO and Escherichia coli WP2

UVRA/PKlOl using rat and hamster liver S9. Gann 75:8-16.

*Archer MC, Lee L, Bruce WR. 1982. Analysis and formation of nitrosamines in

the human intestine. In: Bartsch H et al., ed. IARC Monograph Series No. 41:

N-nitroso compounds: occurrence and biological effects. Lyons, France: WHO,

357-363.

*Atkinson R. 1985. Kinetics and mechanisms of the gas-phase reactions of the

hydroxyl radical with organic compounds under atmospheric conditions. Chem

Rev 85:69-201.

*Atkinson R, Carter WPL. 1984. Kinetics and mechanisms of the gas-phase

reactions of ozone with organic compounds under atmospheric conditions.

Chem Rev 84:437-470.

*Ayanaba A, Alexander M. 1974. Transformation of methylamines and formation

of a hazardous product, dimethylnitrosamine, in samples of treated sewage

and lake water. J Environ Qua1 3:83-89.

*Bakke JP, Mirsalis JC. 1984. Measurement of unscheduled DNA synthesis

(UDS) in fetal and maternal liver following in vivo exposure to genotoxic

agents [abstract]. Environ Mutagen 6:446.

*Bamborschke S, O'Connor PJ, Margison GP, Maru GB, Kleihues P. 1983. DNA

methylation by dimethylnitrosamine in the Mongolian gerbil (meriones

unguiculatus): Implications for a non-inducibe hepatic repair system for 06-

methylguanine. Cancer Res 43:1306-1311.

*Barnes JM, Magee PN. 1954. Some toxic properties of dimethylnitrosamine. Br

J Ind Med 11:167-174.
89

8. REFERENCES

*Barnes D, Bellin J, DeRosa C, et al. 1987. Reference dose (RfD):

description and use in health risk assessments. Volume I, Appendix A:

Integrated risk information system supportive documentation. Washington,

DC: US Environmental Protection Agency, Office of Health and Environmental

Assessment. EPA/600/8-86/032a.

*Bartsch H, Malaveille C, Camus AM et al. 1980. Validation and comparative

studies on 180 chemicals with 2. tynhimurium strains and V79 Chinese hamster

cells in the presence of various metabolizing systems. Mutat Res 76:1-50.

*Bauknecht TH, Vogel W, Bayer U, et al. 1977. Comparative in vivo

mutagenicity testing by SCE and micronucleus induction in mouse bone

marrow. Human Genet 35:299-307.

*Bellar TA, Budde WL, Eichelberger JW. 1979. The identification and

measurement of volatile organic compounds in aqueous environmental samples.

In: Schuetzle D, ed. ACS Symposium Series No. 94. Monitoring toxic

substances. Washington, DC: ACS, 49-62.

*Bermudez E, Mirsalis JC, Eales HC. 1982. Detection of DNA damage in

primary cultures of rat hepatocytes following in vivo and in vitro exposure

to genotoxic agents. Environ Mutagen 4:667-679.

*Bhattacharyya K. 1965. Fetal and Neonatal Responses to hepatotoxic agents.

J Pathol Bacterial 90:151-161.

*Billedeau SM, Thompson HC Jr, Miller BJ, et al. 1986. Volatile

N-nitrosamines in infant pacifiers sold in the United States as determined

by gas chromatography/thermal energy analysis. J Assoc Off Anal Chem 69:31-

34.

*Blazak W, Stewart B, DiBiasio-Erwin D, et al. 1985. Induction of sister

chromatid exchanges (SCE) by dimethylnitrosamine (DMN) in Chinese hamster

cells co-cultured with primary human hepatocytes (PHH) [abstract]. Environ

Mutagen. 7:32.

*Blount JL, Woodruff RC, Hudson SJ. 1985. Interaction between mobile

DNAelementinduced lethal mutations and chemical mutagens in the hybrid

dysgenic system of Drosophila melanozaster. Mutat Res 149:33-40.

*Bolognesi C, Rossi L, Santi L. 1988. A new method to reveal the genotoxic

effects of N-nitrosodimethylamine in pregnant mice. Mutat Res 207:57-62.

*Bontoyan WR, Law MW, Wright DP. Jr., 1979. Nitrosamines in agricultural and

home-use pesticides. J Agr Food Chem 27:631-635.

*Bradley MO, Dysart G, Fitzsimmons K, et al. 1982. Measurements by filter

elution of DNA single- and double-strand breaks in rat hepatocytes: effects

of nitrosamines and gamma-irradiation. Cancer Res 42:2592-2597.
90

8. REFERENCES

*Brambilla G, Cavanna M, Pino A, et al. 1981. Quantitative correlation among

DNA damaging potency of six N-nitroso compounds and their potency in

inducing tumor growth and bacterial mutations. Carcinogenesis 2:425-429.

*Brewer WS, Draper AC III, Wey SS. 1980. The detection of

dimethylnitrosamine and diethylnitrosamine in municipal sewage sludge

applied to agricultural soils. Environ Pollut Ser B Chem Phys 1:37-43.

*Brodberg RK, Mitchell MJ, Smith SL, et al. 1987. Specific reduction of

N,N-dimethylnitrosamine mutagenicity in Drosophila melanozaster by dimethyl

sulfoxide. Environ Mol Mutagen 10:425-432.

*Brunnemann KD, Masaryk J, Hoffmann D. 1983. Role of tobacco stems in the

formation of N-nitrosamines in tobacco and cigarette mainstream and

sidestream smoke. J Agric Food Chem 31:1221-1224.

*Brunnemann KD, Genoble L, Hoffmann D. 1985. N-Nitrosamine in chewing

tobacco: an international comparison. J Agric Food Chem 33:1178-1181.

*Bysshe SB. 1982. Bioconcentration factor in aquatic organisms. In: Lyman

WJ, Reehl WF, Rosenblatt DH, eds. Handbook of chemical property estimation

methods. New York, NY: McGraw Hill Book Co., 5-6

*Callahan MA, Slimak MW, Gabel NW, et al. 1979. Water-related environmental

fate of 129 priority pollutants. Vol. II. Washington, DC: Office of Water

Planning and Standards, Office of Water and Waste Management, U.S. EPA. EPA

440/4-79-029b.

*Canas BJ, Havery DC, Joe FL Jr, et al. 1986. Current trends in levels of

volatile N-nitrosamines in fried bacon and fried-out bacon fat. J Assoc Off

Anal Chem 69:1020-1021.

*Carlton WW, Price PS. 1973, Dietary copper and the induction of neoplasms

in the rat by acetylaminofluorene and dimethylnitrosamine. Fd Cosmet TOXICOL

ii:a27-840.

*Carter RL, Percival WH, Roe FJC. 1969. Exceptional sensitivity of mink to

the hepatotoxic effects of dimethylnitrosamine. J Pathol 97:79-88.

*Carver JH, Salazar EP, Knize MG, et al. 1981. Mutation induction at

multiple gene loci in Chinese hamster ovary cells: The genetic activity of

15 coded carcinogens and noncarcinogens. In: Evaluation of short-term tests

for carcinogens: Report of the International Collaborative program. Prog

Mutat Res 1:594-601.

*CAS (Chemical Abstract Service). 1988. Registry file. On-line: 8:

08/03/88.
91

8. REFERENCES

*Cesarone CF, Bolognesi C, Santi L. 1979. DNA repair synthesis in mice

spermatids after treatment with N-methyl-N-nitroso urea and N-Ndimethylnitrosamine.

Preliminary results. TOXICOL 12:183-186.

*Cesarone CF, Bolognesi C, Santi L. 1982. Evaluation of damage to DNA after

in vivo exposure to different classes of chemicals. Arch Toxicol Suppl

5:355-359.

*Chamberlain WJ, Arrendale RF. 1982. Rapid method for the analysis of

volatile N-nitrosamines in cigarette smoke by glass capillary

chromatography. J Chromatog 234:478-481.

*Clapp NK, Toya RE Sr. 1970. Effect of cumulative dose and dose rate on

dimethylnitrosamine oncogenesis in RF mice. J Nat Cancer Inst 45:495-498.

*Clapp NK, Tyndall RL, Otten JA. 1971. Differences in tumor types and organ

susceptibility in BALB/c and RF mice following dimethylnitrosamine and

diethylnitrosamine. Cancer Res 31:196-198.

*Clive D, Johnson KO, Spector JFS, et al. 1979. Validation and

characterization of the L5178Y/TK+/- mouse lymphoma mutagen assay system.

Mutat Res 59:61-108.

*Cohen JB, Bachman JD. 1978. Measurement of environmental nitrosamines.

IARC Sci Pub1 19:357-372.

*Cohen SZ, Zweig G, Law M, et al. 1978. Analytical determination of

N-nitroso compounds in pesticides by the United States Environmental

Protection Agency A preliminary study. IARC Sci Pub1 19:333-342.

*Cole RH, Frederick RE, Healy RP, et al. 1984. Preliminary findings of the

priority pollutant monitoring project of the nationwide urban runoff

program. J Water Pollut Cont Fed 56:898-908.

*Cooper SW, Kimbrough RD. 1980. Acute dimethylnitrosamine poisoning

outbreak. J Forensic Sci 25: 874-882.

*Cooper SF, Lemoyne C, Gauvreau D. 1987. Identification and quantitation of

N-nitrosamines in human postmortem organs. J Anal Toxicol 11:12-18.

*Crampton RF. 1980. Carcinogenic dose-related response to nitrosamines.

Oncology 37:251-254.

*Crygan P, Greim H, Garro AJ, et al. 1973. Microsomal metabolism of

dimethylnitrosamine and the cytochrome P-450 dependency of its activation to

a mutagen. Cancer Res 33:2983-2986.
92

8. REFERENCES

*Dashman T, Kamm JJ. 1979. Effects of high doses of vitamin E on

dimethylnitrosamine hepatotoxicity and drug metabolism in the rat. Biochem

Pharmacol 28:1485-1490.

*Daugherty JP, Clapp NK. 1976. Studies on nitrosamine metabolism: I.

Subcellular distribution of radioactivity in tumor-susceptible tissues of

RFM mice following administration of (14C)dimethylnitrosamine. Life Sciences

19:265-271.

*De Flora S, Zanacchi P, Camoirano A, et al. 1984. Genotoxic activity and

potency of 135 compounds in the Ames reversion test and in a bacterial

DNArepair

test. Mutat Res 133:161-198.

*Dean-Raymond D, Alexander M. 1976. Plant uptake and leaching of

dimethylnitrosamine. Nature 262:394-396.

*Den Engelse L, Hollander CF, Misdorp W. 1974. A sex-dependent difference in

the type of tumours induced by dimethyl nitrosamine in the livers of C3HF

mice. Eur J Cancer 10:129-135.

*Diaz Gomez MI, Swann PF, Magee PN. 1977. The absorption and metabolism in

rats of small oral doses of dimethylnitrosamine. Biochem J l64:497-500.

*Diaz Gomez MI, Godoy HM, Castro JA. 1981. Further studies on

dimethylnitrosamine metabolism, activation and its ability to cause liver

injury. Arch Toxicol 47:159-168.

*Diaz Gomez MI, Godoy Hm, Villarruel MC, et al. 1983. No response of pigeon

liver to dimethylnitrosamine acute effects. Cancer Lett 18:157-162.

*Diaz Gomez MI, Tamayo D, Castro JA. 1986. Administration of

N-nitrosodimethylamine, N-nitrosopyrrolidine, or N'-nitrosonornicotine to

nursing rats: their interactions with liver and kidney nucleic acids from

sucklings. J Nat1 Cancer Inst 76:1133-1136.

*Dickins M, Wright K, Phillips M, et al. 1985. Toxicity and mutagenicity of

6 anti-cancer drugs in Chinese hamster V79 cells co-cultured with rat

hepatocytes. Mutat Res 157:189-198.

*Doolittle DJ, Bermudez E, Working PK, et al. 1984. Measurement of genotoxic

activity in multiple tissues following inhalation exposure to

dimethylnitrosamine. Mutat Res 141:123-127.

*Dreisch FA, Gower M, Munson TO. 1980. Survey of the Huntington and

Philadelphia river water supplies for purgeable organic contaminants.

Annapolis, MD: U.S. EPA. EPA 903/9-81-003.

*Dropkin D. 1985. Sampling of automobile interiors for organic emissions.

Report. EPA 600/3-85-008. NITS PB85-172567/GAR, 29 pp.
93

8. REFERENCES

*Druckrey H, Preussmann R, Ivankovic S, et al. 1967. [Organotropic

carcinogenic effects of 65 different N-nitroso compounds on BD rats.] Z

Krebsforsch 69:103-201. (German)

*Dunn SR, Pensabene JW, Simenhoff ML. 1986. Analysis of human blood for

volatile N-nitrosoamines by gas chromatography-chemiluminescence detection.

J Chromatog 377:35-47.

*Eichelberger JW, Kerns EH, Olynyk P, et al. 1983. Precision and accuracy in

the determination of organics in water by fused silica capillary column gas

chromatography/mass spectrometry and packed column gas chromatography/mass

spectrometry. Anal Chem 55:1471-1479.

*Eisenreich SJ, Looney BB, Thornton JD. 1981. Airborne organic contaminants

in the Great Lakes ecosystem. Environ Sci Tech 15:30-38.

*Ellis DD, Jone CM, Larson RA, et al'. 1982. Organic constituents of

mutagenic secondary effluents from wastewater treatment plants. Arch

Environ Contam Toxicol. 11:373-382.

*EPA. 1977. Computer print-out of non-confidential production data from

TSCA inventory. Washington, DC. OPTS, CID.

*EPA. 1980a. Guidelines and methodology used in the preparation of health

effect assessment chapters of the consent decree water criteria documents.

US Environmental Protecton Agency. Federal Register 45:79347-79357.

*EPA. 1980. Ambient water quality criteria for nitrosamines. Prepared by the

Office of Health and Environmental Assessment, Environmental Criteria and

Assessment Office, Cincinnati, OH, for the Office of Water Regulations and

Standards, Washington, DC. EPA 440/5-80-064. NTIS PB81-117756, C-48.

*EPA. 1982. Test methods. Methods for organic chemical analysis of municipal

and industrial wastewater. Method No. 607. Cincinnati, OH: Environmental

Monitoring and Support Laboratory, U.S. EPA.

*EPA. 1986. Graphical Exposure Modeling System (GEMS). PCCHEM computer

program.

*EPA. 1987. 40 CFR Parts 300 and 355. Extremely hazardous substances list

and threshold planning quantities; emergency planning and release

notification requirements. Final rule. Fed Reg 52:13378-13410.

*EPA. 1988a. Integrated Risk Information System (IRIS). Risk Estimate for

carcinogenicity for N-Nitrosodimethylamine. Online. (Verification data

03/01/88.) Office of Health and Environmental Assessment, Environmental

Criteria and Assessment Office, Cincinnati, OH.
94

8. REFERENCES

*EPA. 1988b. Storage and Retrieval Water Quality Data Base (STORET) Online:

09/06/88

*Fajen JM. 1980. Industrial hygiene study of workers exposed to

nitrosamines. In: Proceedings of the first NCI/EPA/NIOSH collaborative

workshop: Progress on joint environmental and occupational cancer studies,

May 6-8, Rockville, MD.

*Fajen JM, Rounbehler DP, Fine DH. 1982. Summary report on N-nitrosamines in

the factory environment. In: Bartsch H et al, ed. IARC Monograph Series No.

41, N-nitroso compounds: occurrence and biological effects. Lyons, France:

WHO, 223-230.

*Faustman E. 1989. Written communication to ATSDR (September 7, 1989).

*Fazio T, Havery DC. 1982. Volatile N-nitrosamines in direct flame-dried

processed foods. In: IARC Sci Pub1 41:277-286.

*Federal Register. 1981. Notice: FDA action level for

N-nitrosodimethylamine in barley malt; availability of guide. 46:39218-

39219.

*Federal Research in Progress. 1988. On-line: July 1988. Dialog File 165.

Dialog Information Services, Inc.

*Fiddler W, Pensabene JW, Doerr RC, et al. 1977. The presence of dimethyland

diethyl-nitrosamines in deionized water. Fd Cosmet Toxicol 15:441-443.

*Fiddler W, Pensabene JW, Kimoto WI. 1981. Investigations of edible oils for

volatile nitrosamines. J Food Science 46:603-605.

*Fine DH. 1982. Presence of nitrosamines in human beings. In: Magee PN, ed.

Banbury Report: Nitrosamines and human cancer, Vol. 12. Cold Spring Harbor,

NY, Cold Spring Harbor Laboratory, 271-281.

*Fine DH, Rounbehler DP, Belcher NM, et al. 1976a. N-Nitroso compounds:

detection in ambient air. Science 192:1328-1330.

*Fine DH, Rounbehler DP, Pellizzari ED, et al. 1976b. N-Nitrosodimethylamine

in air. Bull Environ Cont Tox 15:739-746.

*Fine DH, Rounbehler DP, Sawicki E, et al. 1977a. Determination of

dimethylnitrosamine in air and water by thermal energy analysis: validation

of analytical procedures. Environ Sci Technol 11:577-580.

*Fine DH, Rounbehler DP, Rounbehler A, et al. 1977b. Determination of

dimethylnitrosamine in air, water, and soil by thermal energy analysis:

measurements in Baltimore, MD. Environ Sci Technol 11:581.584.
95

8. REFERENCES

*Fine DH, Rounbehler DP, Fan T, Ross R. 1977c. Human exposure to N-nitroso

compounds in the environment. In: Hiatt HH, Watson JD, Winsten JA, eds.

Origins of human cancer. Book A: Incidence of cancer in humans. Cold Spring

Laboratory, 293-307.

*Fisher RL, Reiser RW, Lasoski BA. 1977. Determination of sub-microgram per

cubic meter levels of N-nitrosodimethylamine in air. Anal Chem 49:1821-1823.

*Frank CW, Berry CM. 1981. N-Nitrosamines. In: Clayton GD, Clayton FE, eds.

Patty's industrial hygiene and toxicology. 3rd ed. New York, NY: John Wiley

& Sons, 3117-3133.

*Freund HA. 1937. Clinical manifestations and studies in parenchymatous

hepatitis. Ann Int Med 10:1144-1155.

*Frezza D, Smith B, Zeiger E. 1983. The intrasanguineous host-mediated

assay procedure using Saccharomvces cerevisiae: comparison with two other

metabolic activation systems. Mutat Res 108:161-168.

*Friedman MA, Sanders V. 1976. Acute toxicity of dimethylnitrosamine in the

presence of inhibitors of DMN demethylase. Experientia 32:495-496.

*Friedman MA, Staub J. 1976. Inhibition of mouse testicular DNA synthesis by

mutagens and carcinogens as a potential simple mammalian assay for

mutagenesis. Mutat Res 37:67-76.

*FSTRAC (Federal-State Toxicology and Regulatory Alliance Committee). 1988.

Summary of State and Federal drinking water standards and guidelines.

Chemical Communication Subcommittee, March 10, 17.

Fumero S, Mellano D, Peano S, et al. 1985. Micronucleus induction in rat

fetal blood by DMNA directly injected into the fetus [abstract]. Mutat Res

147:295.

*Fussgaenger RD, Ditschuneit H. 1980. Lethal exitus of a patient with

N-Nitrosodimethylamine poisoning 2.5 years following the first ingestion and

signs of intoxication. Oncol 37:273-277.

*Garland WA, Kuenzig W, Rubio FU, et al. 1986. Urinary excretion of

nitrosodimethylamine and nitrosoproline in humans: interindividual and

intraindividual differences and the effect of administered ascorbic acid and

alpha-tocopherol. Cancer Res 46:5392-5400.

*Gellert J, Moreno F, Haydn M, et al. 1980. Decreased hepatotoxicity of

dimethylnitrosamine (DMN) following chronic alcohol consumption. Adv Exp med

Biol 132:237-243.

*Geyer H, Scheunert I, Korte F. 1986. Bioconcentration potential of organic

environmental chemicals in humans. Regul Toxicol Pharmacol 6:313-347.
96

8. REFERENCES

*Gaff EU, Fine DH. 1979. Analysis of volatile N-nitrosamines in alcoholic

beverages. Fd Cosmet Toxicol 17:569-573.

*Gordon RJ. 1978. Survey for airborne nitrosamines [Abstract]. Gov Rep

Announce Index 79:65.

*Gough TA, Webb KS, McPhail MF. 1977. Volatile nitrosamines from ionexchange

resins. Fd Cosmet Toxicol 15:437-440.

*Gough TA, Webb KS, Swann PF. 1983. An examination of human blood for the

presence of volatile nitrosamines. Fd Chem Toxicol 21:151-156.

*Greene S, Alexander M, Leggett D. 1981. Formation of

N-nitrosodimethylamine during treatment of municipal waste water by

simulated land application. J Environ Qua1 10:416-421.

*Griciute L, Castegnaro M, Bereziat JC. 1981. Influence of ethyl alcohol on

carcinogenesis with N-nitrosodimethylamine. Cancer Lett 13:345-352.

*Groenen PJ, de Cock-Bethbeder MW, Bouman J. et al. 1980. Formation of

N-nitrosamines and N-nitrosamino acids from food products and nitrite under

simulated gastric conditions. Proc of the VIth Intern Symp on N-Nitroso

Compounds International Agency for Research on Cancer (IARC) Lyon.

*Hadjiolov D, Mundt D. 1974. Effect of aminoacetonitrile on the metabolism

of dimethylnitrosamine and methylation of RNA during liver carcinogenesis. J

Nat1 Cancer Inst 52:753-756.

*Hamilton A, Hardy HL. 1974. Industrial Toxicology. Third Edition

Publishing Science Group, Inc. Acton, MA. p. 311.

*Hansch C, Leo AJ. 1985. Medchem project issue no. 26. Claremont, CA,

Pomona College.

*Hanst PL, Spence JW, Miller M. 1977. Atmospheric chemistry of

N-nitrosodimethylamine. Environ Sci Technol 11:403-405.

*Hard GC, Butler WI-I. 1970. Toxicity of dimethylnitrosamine for the rat

testis. J Pathol 102:201-207.

*Hashimoto S, Yokokura T, Kawai Y, et al. 1976. Dimethylnitrosamine

formation in the gastro-intestinal tract of rats. Fd Cosmet Toxicol 14:553-

556.

*Havery DC, Hotchkiss JH, Fazio T. 1981. Nitrosamines in malt and malt

beverages. J Food Sci 46:501-505.
97

8. REFERENCES

*Havery DC, Perpetti GA, Canas BJ, et al. 1985. Reduction in levels of ,

volatile N-nitrosamines in rubber nipples for babies' bottles. Fd Chem

Toxicol 23:991-993.

*Hawley GG. 1981. The condensed chemical dictionary. 10th ed. New York, NY.

Van Nostrand Reinhold Company, Inc., 737.

*Heading CE, Phillips JC, Lake BG et al. 1974. Some aspects of the

metabolism of dimethylnitrosamine in the rat. Biochem Sot Trans 2:607-610.

*Heath DF. 1962. The decomposition and toxicity of dialkyinitrosamines in

rats. Biochem J 85:72-91.

*Hemminki K. 1982. Dimethylnitrosamine adducts excreted in rat urine. ChemBiol Interact 39:139-148.

*Herron DC, Shank RC. 1980. Methylated purines in human liver DNA after

probable dimethylnitrosamine poisoning. Cancer Res 40:3116-3117.

*Hindle RW, Armstrong JF, Peake AA. 1987. Determination of

N-nitrosodimethylamine levels in some Canadian 2,4-D amine formulations. J

Assoc Off Anal them 70:49-51.

*Hoffman D,Adams JD, Brunnemann KD. 1987. A critical look at N-nitrosamines

in environmental tobacco smoke. Toxicol Lett 35:1-8.

*Holsapple MP, Munson AE, McNerney P, et al. 1983. Immunosuppression by

subchronic exposure to dimethylnitrosamine in female B6C3Fl mice. In: 67th

annual meeting of the Federation of American Societies for Experimental

Biology, Chicago, IL, April 10-15. Fed Proc 42:abstract 469.

*Holsapple MP, Tucker AN, McNerney PJ, et al. 1984. Effects of

N-nitrosodimethylamine on humoral immunity. J Pharmacol Exp Ther 229:493-

500.

*Holsapple MP, Bick PH, Duke SS. 1985. Effects of N-nitrosodimethylamine on

cell-mediated immunity. J Leukocyte Biol 37:367-381.

*Hotchkiss JH, Havery DC, Fazio T. 1981. Rapid method for estimation of

N-nitrosodimethylamine in malt beverages. J Assoc Off Anal Chem 64:929-

932.

*HSDB. 1988. Hazardous Substance Data Base. Record no. 1667. On-line

08/19/88.

*Hsie AW, Machanoff R, Couch DB, et al. 1978. Mutagenicity of

dimethylnitrosamine and ethyl methanesulfonate as determined by the

hostmediated

CHO/HGPRT assay. Mutat Res 51:77-84.
98

8. REFERENCES

*Huang DP, Ho, JHC, Webb KS, et al. 1981. Volatile nitrosamines in

saltpreserved

fish before and after cooking. Fd Cosmet Toxicol. 19:167-172.

*IARC (International Agency for Research on Cancer). 1978. IARC monographs

on the evaluation of the carcinogenic risk of chemicals to humans. Some

N-nitroso compounds Vol. 17. p. 125-175.

*IARC (International Agency for Research on Cancer). 1982. Laboratory

decontamination and destruction of carcinogens in laboratory wastes: Some

N-nitrosoamines. IARC Scientific Publication No. 43.

IARC (International Agency for Research on Cancer). 1984. N-nitroso

compounds: Occurrence, biological effects and relevance to human cancer.

IARC Scientific Publication No. 57.

*IARC (International Agency for Research on Cancer). 1987a. IARC

monographs on the evaluation of carcinogenic risks to humans. Update of

IARC Monographs Vols l-42, Suppl 7, 31-32, 67-68.

IARC (International Agency for Research on Cancer). 1987b. The relevance

of N-nitroso compounds to human cancer. Exposures and mechanisms. IARC

Scientific Publication No. 84.

*Ikeuchi T, Sasaki M. 1981. Differential inducibility of chromosome

aberrations and sister-chromatid exchanges by indirect mutagens in various

mammalian cell lines. Mutat Res 90:149-161.

*Imbriani M, Ghittori S, Pezzagno G, et al. 1985. Urine/air partition

coefficients for some industrially important substances. G Ital Med Lav

7;133-40.

*Inoue K, Shibata T, Abe T. 1983. Induction of sister-chromatid exchanges in

human lymphocytes by indirect carcinogens with and without metabolic

activation. Mutat Res 117:301-309.

*Inui N, Nishi Y, Taketomi M, et al. 1979. Transplacental action of sodium

nitrite on embryonic cells of Syrian golden hamster. Mutat Res 66:149-158.

*Ireton HJC, McGiven AR, Davies DJ. 1972. Renal mesenchymal tumour induced

in rats by dimethylnitrosamine: light- and electron-microscope studies. Path

108:181.

*IRPTC (International Register of Potentially Toxic Chemicals). 1988.

United Nations Environment Programme. Geneva, Switzerland: IRPTC/UNEP.

*Ishidate M. Jr., Yoshikawa K. 1980. Chromosome aberration tests with

Chinese hamster cells in vitro with and without metabolic activation: A

comparative study on mutagens and carcinogens. In: Further studies in the

assessment of toxic actions. Arch Toxicol Suppl 4:41-44.
99

8. REFERENCES

*Ishinishi N, Tanaka A, Hisanaga A, et al. 1988. Comparative-study on the

carcinogenicity of N-nitrosodiethylamine, N-nitrosodimethylamine,

N-nitrosomorpholine, N-nitrosopyrrolidine and N-nitrosodi-n-propylamine to

the lung of Syrian golden hamsters following intermittent instillations to

the trachea. Carcinogenesis 9:947-950.

*Ishiwata H, Mizushiro H, Tanimura A, et al. 1977. Metabolic fate of the

precursors of N-nitroso compounds. I. Gastro-intestinal absorption of

N-nitrosodimethylamine and its precursors in guinea-pigs. J Fd Hyg Sot

18:524-528.

*Ito N, Fukushima S, Tsuda H, et al. 1982. Induction of preneoplastic and

neoplastic lesions in rats treated N-nitroso compounds. IARC Sci Pub1

41:597-601.

*Iversen OH. 1980. Tumorigenicity of N-nitroso-diethyl, -dimethyl and -

diphenyl-amines in skin painting experiments. A study utilizing the

tetrazolium test and skin applications on hairless mice. Eur J Cancer

16:695-698.

*Jacobson KH, Wheelwright HJ Jr, Clem JH, et al. 1955. Studies on the

toxicology of N-nitrosodimethylamine vapor. AMA Arch Indust. Health 12:

617-622.

*Jagannath DR, Vultaggio DM, Brusick DJ. 1981. Genetic activity of 42 coded

compounds in the mitotic gene conversion assay using Saccharomvces

cerevisiae strain D4. In: Evaluation of short-term tests for carcinogens:

Report of the International collaborative Program. Prog Mutat Res 1:456-467.

*Jenkins SA, Grandison A, Baxter JN, et al. 1985. A dimethylnitrosamineinduced

model of cirrhosis and portal hypertension in the rat. J Hepatol

1:489-499.

*Johansson EB, Tjalve H. 1978. The distribution of (14C)dimethylnitrosamine

in mice. Autoradiographic studies in mice with inhibited and noninhibited

dimethylnitrosamine metabolism and a comparison with the distribution of

(14C)formaldehyde. Toxicol Appl Pharmacol 45:565-575.

*Johnson KW, Munson AE, Holsapple MP. 1987a. Primary cellular target

responsible for dimethylnitrosamine-induced immunosuppression in the mouse.

Immunopharmacology 13:47-60.

*Johnson KW, Munson AE, Kim D-H, et al. 1987b. Role of reactive metabolites

in suppression of humoral immunity by N-nitrosodimethylamine. J. Pharmacol

Exp Ther 240:847-855.
100

8. REFERENCES

*Kaminski NE, Jordan SD, Page D., et al. 1989. Suppression of humoral

immune responses by dialkylnitrosamines: Structure-activity relationships.

Fund Appl Toxicol 12:321-332.

*Kaplan DL, Kaplan AM. 1985. Biodegradation of N-nitrosodimethylamine in

aqueous and soil systems. Appl Environ Microbial 50:1077-1086.

*Katoh Y, Tanaka M, Takayama S. 1982. Higher efficiency of hamster

hepatocytes than rat hepatocytes for detecting dimethylnitrosamine and

diethylnitrosamine in hepatocyte-mediated Chinese hamster V79 cell

mutagenesis assay, Mutat Res 105:265-269.

*Keefer LK. 1989. Written communication (May 1) to Stephen Bosch, Syracuse

Research Corporation, Syracuse, NY, regarding on-going metabolism studies.

Department of Health and Human Services, Public Health Service, National

Institutes of Health, National Cancer Institute, Frederick Cancer Research

Facility, Frederick, MD.

*Keefer LK, Lijinsky W, Garcia H. 1973. Deuterium isotope effect on the

carcinogenicity of dimethylnitrosamine in rat liver. J Nat1 Cancer Inst

51:299-302.

*Keefer LK, Anjo T, Heur YH, et al, 1987. Potential for metabolic

deactivation of carcinogenic N-nitrosodimethylamine in vivo. IARC Sci Pub1

84:113-116.

*Khanna SD, Puri D. 1966. The hepatotoxic effects of dimethylnitrosamine in

the rat. J Path Bact 91:605-608.

*Khudoley V, Malaveille C, Bartsch H. 1981. Mutagenicity studies in

Salmonella tvnhimurium on some carcinogenic N-nitrosoamines in vitro and in

the host-mediated assay in rats. Cancer Res 41:3205-3210.

*Kimbrough RD. 1982. Pathological changes in human beings acutely poisoned

by dimethylnitrosamine. In: Magee PN, ed. Banbury Report, Vol. 12.

Nitrosamines and human cancer; meeting. Cold Spring Harbor, NY: Cold Spring

Harbor Laboratory, 25-36.

*Kimoto WI, Dooley CJ, Carre J, et al. 1981. Nitrosamines in tap water

after concentration by a carbonaceous adsorbent. Water Res 15:1099-1106.

*Kimoto WI, Silbert LS, Fiddler W. 1984. Confirmation of

N-nitrosodimethylamine and N-nitrosopyrrolidine in foods by conversion to

their nitramines with pentafluoroperoxybenzoic acid. J Assoc Off Anal Chem

67:751-756.

*Klein RG. 1982. Calculations and measurements on the volatility of

N-nitrosoamines and their aqueous solutions. Toxicology 23:135-147.
101

8. REFERENCES

*Klein RG, Schmezer P. 1984. Quantitative measurement of the exhalation

rate of volatile N-nitrosamines in inhalation experiments with anesthetized

Sprague-Dawley rats. IARC Sci Pub1 57:513-517.

*Kobayashi M, Tchan YT. 1978. Formation of dimethylnitrosamine in polluted

environment and the role of photosynthetic bacteria. Water Res 12:199-201.

*Koppang N, Rimeslatten H. 1976. Toxic and carcinogenic effects of

nitrosodimethylamine in mink. IARC Sci Pub1 14:443-452.

*Kornbrust D, Dietz D. 1985. Aroclor 1254 pretreatment effects on DNA

repair in rat hepatocytes elicited by in vivo and in vitro exposure to

various chemicals. Environ Mutagen 7:857-870.

*Korsrud GO, Grice HG, Goodman TK, et al. 1973. Sensitivity of several

serum enzymes for the detection of thioacetamide, dimethylnitrosamine-and

diethanolamine-induced liver damage in rats. Tox Appl Pharm 26:299-313.

*Kosaka H, Uozumi M. Nakajima T. 1984. Measurement of nitrosodimethylamine

by capillary gas chromatography-mass spectrometry with the 15N-labelled

compound as an internal standard. Int Arch Occ Environ Health 54:233-239.

*Kroeger-Koepke MB, Michejda CJ. 1979. Evidence for several demethylase

enzymes in the oxidation of dimethylnitrosamine and phenylmethylnitrosamine

by rat liver fractions. Cancer Res 39:1587-1591.

*Kuroki T, Drevon C, Montesano R. 1977. Microsome-mediated mutagenesis in

V79 Chinese hamster cells by various nitrosamines. Cancer Res 37;1044-1050.

*Lakritz L, Simenhoff ML, Dunn SR, et al. 1980. N-Nitrosodimethylamine in

human blood. Fd Cosmet Toxicol 18:77-79.

*Lakritz L, Pensabene JW. 1981. Survey of fluid and nonfat dry milks for

N-nitrosamines. J Dairy Sci 64:371-374.

*Lakritz L, Pensabene JW. 1984. Survey of human milk for volatile

N-nitrosamines and the influence of diet on their formation. Fd Chem

Toxicol 22:721-724.

*Landon EJ, Naukam RJ, Rama Sastry BV. 1986. Effects of calcium channel

blocking agents on calcium and centrilobular necrosis in the liver of rats

treated with hepatotoxic agents. Biochem Pharmacol 35:697-705.

*Langenbach R. 1986. Mutagenic activity and structure-activity

relationships of short-chain dialkyl N-nitrosamines in a hamster hepatocyte

V79 cell-mediated system. Mutat Res 163:303-311.
102

8. REFERENCES

*Langenbach R, Leavitt S, Hix C, et al. 1986. Rat and hamster

hepatocytemediated

induction of SCEs and mutation in V79 cells and mutation of

Salmonella by aminofluorene and dimethylnitrosamine. Mutat Res 161:29-37.

*Lawrence JF, Weber DF. 1984. Determination of polycyclic aromatic

hydrocarbons in Canadian samples of processed vegetable and dairy products

by liquid chromatography with fluorescence detection. J Agric Food Chem

32:794-797.

*Lee WR, Abrahamson S, Valencia R. et al. 1983. The sex-linked recessive

lethal test for mutagenesis in Drosophila melanogaster. A report of the U.S.

Environmental Protection Agency Genetox Program. Mut Res 123:183-279.

*Lele PS, Dunn SR, Simenhoff ML, et al. 1983. Evidence for generation of the

precarcinogen nitrosodimethylamine in the small intestine in chronic renal

failure. Kidney Int 24 suppl 16:S229-S233.

*Lele P, Dunn SR. Simenhoff ML. 1985. Demonstration of the carcinogen

dimetylnitrosamine (DMNA) generation in gut by ethanol inhibition of its

first-pass metabolism by liver in chronic renal failure [abstract], Kidney

Int 27:245.

*Lele PS, Dunn SR, Simenhoff ML. 1987. Nutritional and metabolic modulation

of the carcinogen nitrosodimethylamine in chronic renal failure. Kidney Int

32, suppl 22:S-159-S-161.

*Lijinsky W, Reuber MD. 1981. Comparative carcinogenesis by some aliphatic

nitrosamines in Fischer rats. Cancer Lett 14:297-302.

*Lijinsky W. 1987. Structure-activity relations in carcinogens by N-nitroso

compounds. Cancer Metastasis Rev 6:301-356.

*Lijinsky W, Kovatch RM, Riggs CW. 1987. Carcinogenesis by

nitrosodialkylamines and azoxyalkanes given by gavage to rats and hamsters.

Cancer Res. 47:3968-3972.

*Lijinsky W, Reuber MD. 1984. Carcinogenesis in rats by

nitrosodimethylamine and other nitrosomethylalkylamines at low doses.

Cancer Lett 22:83-88.

Lijinsky W. 1986. The significance of N-nitroso compounds on environmental

carcinogens. J Environ Sci Health C4(1):1-45.

*Lorr NA, Miller KW, Chung HR, et al. 1984. Potentiation of the

hepatotoxicity of N-nitrosodimethylamine by fasting, diabetes, acetone, and

isopropanol. Toxicol Appl Pharmacol 73:423-431.
103

8. REFERENCES

*Lotlikar PD, Baldy WJ Jr, Dwyer EN. 1975. Dimethylnitrosamine

demethylation by reconstituted liver microsomal cytochrome P-450 enzyme

system. Biochem J 152:705-708.

*Lotlikar PD, Hong YS, Baldy WS Jr. 1978. Effect of dimethylnitrosamine

concentration on its demethylation by liver microsomes from control and 3-

methylcholanthrene pretreated rats, hamster and guinea pigs. Cancer Lett

4:355-361.

Lu SH, Yang WX, Guo LP, et al. 1987. Determination of N-nitrosamines in

gastric juice and urine and a comparison of endogenous formation of

N-nitrosoproline and its inhibition in subjects from high-and low-risk

areas for oesophageal cancer. IARC Sci Pub1 84:538-543.

*Luster MI, Blank JA, Dean JH. 1987. Molecular and cellular basis of

chemically induced immunotoxicity. Ann Rev Pharmacol Toxicol 27:23-49.

*Luster MI, Munson AE, Thomas PT, et al. 1988. Method Evaluation.

Development of a testing battery to assess chemical-induced immunotoxicity

National Toxicology Program's guidelines for immunotoxicity evaluation in

mice. Fund Appl Toxicol 10:2-19.

*Lyman WJ. 1985. Estimation of physical properties. In: Neely WB, Blau GE,

eds. Environmental exposure from chemicals, Vol. 1, Boca Raton, FL: CRC

Press Inc., 30-31.

*Lyman WJ. 1982. Adsorption coefficient for soils and sediments. In: Lyman

WJ, Reehl WF, Rosenblatt DH, eds. Handbook of chemical property estimation

methods. New York, NY: McGraw-Hill Book Co., 4-9

*Madle E, Kasper P, Madle S, et al. 1987. Hepatocyte-mediated SCE induction

by indirect mutagens: Importance of hepatocyte density and cell-to-cell

contact. Mutat Res 188:153-160.

*Maduagwu EN, Bassir 0. 1980. A comparative assessment of toxic effects of

dimethylnitrosamine in six different species. Toxicol Appl Pharmacol

53:211-219.

*Magee PN. 1956. Toxic liver injury: The metabolism of dimethylnitrosamine.

Biochem J 64:676-682.

*Magee PN, Barnes JM. 1956. The production of malignant primary hepatic

tumours in the rat by feeding dimethylnitrosamine Br J Cancer 10:114-122.

*Magee PN, Montesan R, Preussman R. 1976. N-nitroso compounds and related

carcinogens. ACS Monograph 173:491-625.
104

8. REFERENCES

*Maling HM, Stripp B, Sipes IG, et al. 1975. Enhanced hepatotoxicity of

carbon tetrachloride, thioacetamide, and dimethylnitrosamine by

pretreatment of rats with ethanol and some comparisons with potentiation by

isopropanol. Toxicol Appl Pharmacol 33:291-308.

*Mallik MAB, Tesfai K. 1981. Transformation of nitrosamines in soil and in

vitro by soil microorganisms. Bull Environ Contam Toxicol 27:115-121.

*Martelli A, Robbiano L, Giuliano L, et al. 1985. DNA fragmentation by

N-nitrosodimethylamine and methyl methanesulfonate in human hepatocyte

primary cultures. Mutat Res 144:209-211.

*Martin0 PE, Diaz Gomez MI, Tamayo D, et al. 1988. Studies on the mechanism

of the acute and carcinogenic effects of N-nitrosodimethylamine on mink

liver. J Toxicol Environ Health 23:183-192.

*Massey RC, Key PE, McWeeny DJ.,Jr. et al. 1987. An investigation of

apparent total N-nitroso compounds in beer. In: Relevance of N-nitroso

compounds to Human Cancer. Exposures and Mechanisms. IARC Sci Pub1 84:219-

221.

*Matsuoka A, Hayashi M, Ishidate M., Jr. 1979. Chromosomal aberration tests

on 29 chemicals combined with S9 mix in vitro. Mutat Res 66:277-290.

*Matsuoka A, Sofuni T, Ishidate M. 1986. Effect of surfactants on the

induction of chromosomal aberrations in Chinese hamster cells in culture

[Abstract]. Mutat Res 164:273-274.

*McCormick A, Nicholson MJ, Baylis MA, et al. 1973. Nitrosamines in

cigarette smoke condensate. Nature 244:237-238.

*McGiven AR, Ireton HJC. 1972. Renal epithelial dysplasia and neoplasia in

rats given dimethylnitrosamine. J Pathol 108:187-190.

*McQueen CA, Kreiser DM, Williams GM. 1983. The hepatocyte primary

culture/DNA repair assay using mouse or hamster hepatocytes. Environ

Mutagen 5:1-8.

*Mehta R, Silinskas KC, Zucker PF, et al. 1987. Micronucleus formation

induced in rat liver and esophagus by nitrosamines. Cancer Lett 35:313-

320.

*Mills AL, Alexander M. 1976. Factors affecting dimethylnitrosamine

formation in samples of soil and water. J Environ Qua1 5:437-440.
105

8. REFERENCES

*Mirvish SS, Issenberg P, Sornson HC. 1976. Air-water and ether-water

distribution of N-nitroso Compound: Implications for laboratory safety,

analytic methodology, and carcinogenicity for the rat esophagus, nose, and

liver. J Nat1 Cancer Inst 56:1125-1129.

*Moiseev GE, Benemanskii V. 1975. [Concerning the carcinogenic activity of

low concentrations of nitrosodimethylamine during inhalation.] Vopr Onkol

(Leningr) 21:107-109. (Russian)

*Montesano R, Bresil H, Pegg AE. 1982. Metabolism of dimethylnitrosamine and

repair of 0-6-methylguanine in DNA by human liver. In: Magee PN, ed. Banbury

report, Vol. 12, Nitrosamines and human cancer. Cold Spring Harbor, NY: Cold

Spring Harbor Laboratory, 141-152.

*Mufti SI, Salvagnini M, Lieber CS, et al. 1988. Chronic ethanol consumption

inhibits repair of dimethylnitrosamine induced DNA alkylation, Biochem

Biophys Res Corn 152:423-441.

*Mumma RO, Raupach DC, Waldman JP, et al. 1984. National survey of elements

and other constituents in municipal sewage sludges. Arch Environ Contam

Toxicol 13:75-83.

*Myers MJ, Pullen JK, Schook LB. 1986. Alteration of macrophage

differentiation into accessory and effector cells from exposure to

dimethylnitrosamine (DMN) in vivo. Immunopharmacology 12:105-115.

*Myers MJ, Dickens CS, Schook LB. 1987. Alteration of macrophage antitumor

activity and transferrin receptor expression by exposure to

dimethylnitrosamine in vivo. Immunopharmacology 13:195-205.

*Napalkov NP, Alexandrov VA. 1968. On the effects of blastomogenic

substances during embryogenesis. Z Krebsforsch 71:32-50.

*NATICH (National Air Toxics Information Clearinghouse). 1987. NATICH data

base report on state, local and EPA air toxics activities, 101.

*Neal SB, Probst GS. 1983. Chemically-induced sister chromatid exchange in

vivo in bone marrow of Chinese hamsters. An evaluation of 24 compounds.

Mutat Res 113:33-43.

*Neurath GB, Duenger M, Pein FG, et al. 1977. Primary and secondary amines

in the human environment. Fd Cosmet Toxicol 15:275-282.

*Ng WL, Fong LYY, Newberne PM. 1984. Forestomach squamous papillomas in the

rat: effect of dietary zinc deficiency on induction. Cancer Lett 22:329-332.

*NIOSH. 1988. National Occupational Exposure Survey (NOES) as of May 10,

1988. Washington, DC: National Institute for Occupational Safety and Health.
106

8. REFERENCES

*Nishie K. 1983. Comparison of the effects of N-nitrosodimethylamine on

pregnant and nonpregnant Holtzman rats. Fd Chem Toxicol 21:453-462.

*Nishie K, Norred WP, Wasserman A, et al. 1972. Phototoxicity and

differential hepatotoxicity as biological indicators of nitrosamine

activity. Toxicol Appl Pharmacol 23:680-691.

*O'Connor PJ, Chu Y-H, Cooper DP, Maru GB, Smith RA Margison GP. 1982.

Species difference in the inducibility of hepatic 06

 -alkylguanine repair in

rodents. Biochimie 64:769-773.

*Odagiri Y, Adachi S, Katayama H, et al. 1986. Detection of the cytogenetic

effect of inhaled aerosols by the micronucleus test. Mutat Res 170:79-83.

*O'Neill JP, Machanoff R, San Sebastian JR, et al. 1982. Cytotoxicity and

mutagenicity of dimethylnitrosamine in mammalian cells (CHO/HGPRT system):

Enhancement by calcium phosphate. Environ Mutagen 4:7-18.

*OHM-TADS. (Oil and Hazardous Materials Technical Assistance Data System).

1988. Computer data base. On-line: July 31, 1988.

*Ohta T, Suzuki J, Iwano Y, et al. 1982. Photochemical nitrosation of

dimethylamine in aqueous solution containing nitrite. Chemosphere 11:797-

801.

*Okinaka RT, Barnhart BJ, Chen DJ. 1981. Comparison between sisterchromatid

exchange and mutagenicity following exogenous metabolic activation

of promutagens. Mutat Res 91:57-61.

*Oliver JE. 1979. Volatilization of some herbicide-related nitrosamines

from soils. J Environ Qua1 8:596-601.

*Oliver JE, Kearney PC, Kontson A. 1979. Degradation of herbicide-related

nitrosamines in aerobic soils. J. Agric Food Chem 27:887-891.

*Omori Y, Takahashi A, Ohno Y, et al. 1979. Drug-nitrite interactions:

Species and sex differences in the formation of dimethylnitrosamine and its

effects on the hepatic enzyme activities. Arch Toxicol Suppl 2:349-354.

*Otsuka H, Kuwahara A. 1971. Hemangiomatous lesions of mice treated with

nitrosodimethylamine. Gann 62:147-156.

*Page GW. 1981. Comparison of groundwater and surface water for patterns and

levels of contamination by toxic substances. Environ Sci Technol 15:1475-

1481.

*Pancholy SK. 1978. Formation of carcinogenic nitrosamines in soils. Soil

Biol Biochem 10:27-32.
107

8. REFERENCES

*Pedal I, Besserer K, Goerttler K, et al. 1982. Fatal nitrosamine poisoning.

Arch Toxicol 50:101-112.

*Pegg AE. 1980. Metabolism of N-Nitrosodimethylamine. IARC Sci Pub1 27:3-22.

*Pegg AE, Hui G. 1978. Removal of methylated purines from rat liver DNA

after administration of dimethylnitrosamine. Cancer Res 38:2011-2017.

*Pegg AE, Perry W. 1981. Alkylation of nucleic acids and metabolism of

small doses of dimethylnitrosamine in the rat. Cancer Res 41:3128-3132.

*Pegg AE, Perry W, Bennett RA. 1981. Effect of partial hepatectomy on

removal of 06

-methylguanine from alkylated DNA by rat liver extracts.

Biochem J 197:195-201.

*Pensabene JW, Miller AJ, Greenfield EL, et al. 1982. Rapid dry column

method for determination of N-nitrosopyrrolidine in fried bacon. J Assoc Off

' Anal Chem 65:151-156.

*Pensabene JW, Fiddler W. 1988. Determination of volatile N-nitro-.amine in

frankfurters containing minced fish and surimi. J Assoc Off Anal Chem

71:839-843.

*Pet0 R, Gray R, Brantom P, et al. 1984. Nitrosamine carcinogenesis in 5120

rodents: Chronic administration of sixteen different concentrations of

NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats with parallel

studies on NDEA alone of the effect of age of starting (3, 6 or 20 weeks)

and of species (rats, mice or hamsters). IARC Sci Pub1 57:627-666.

*Petzold GL, Swenberg JA. 1978. Detection of DNA damage induced in vivo

following exposure of rats to carcinogens. Cancer Res 38:1589-1594.

*Phillips JC, Lake BG, Heading CE, et al. 1975. Studies on the metabolism of

dimethylnitrosamine in the rat: I. Effect of dose, route of administration

and sex. Fd Cosmet Toxicol 13:203-209

*Pignatelli B, Richard I, Bourgade M, et al. 1987. An improved method for

analysis of total N-nitroso compounds in gastric juice In: Relevance of

N-nitroso compounds to Human Cancer: Exposures and Mechanisms. IARC Sci Pub1

84:209-215.

*Poirier S, G Hubert, de-The H et al. 1987. Occurrence of volatile

nitrosamines in food samples collected in three high-risk areas for

nasopharyngeal carcinoma. IARC Sci Pub1 84:415-419.

*Polo J, Chow UL. 1976. Efficient photolytic degradation of nitrosamines. J

Nat1 Cancer Inst 56:997-1001.
108

8. REFERENCES

*Prasanna HR, Lotlikar PD, Barndt C, et al. 1985. Factors influencing the

activity of dimethylnitrosamine demethylase in hamster, rat and chicken

liver microsomes. Cancer Lett 26:25-32.

*Preussmann R. 1984. Occurrence and exposure to N-nitroso compounds and

precursors. IARC Sci Publ. 57:3-15.

*Prival MJ, Mitchell VD. 1981. Influence of microsomal and cytosolic

fractions from rat, mouse, and hamster liver on the mutagenicity of

dimethylnitrosamine in the Salmonella plate incorporation assay. Cancer Res

41:4361-4367.

*Pylypiw HM Jr. 1987. The development and application of analytical methods

for the study of volatile and non-volatile N-nitrosamines

(Pharmacokinetics). Disser Abstr Inter 48:1028-B.

*Pylypiw HM Jr., Zimmerman F, Harrington GW, et al. 1985. Apparatus for

trace determination of volatile N-nitrosamines in small samples. Anal Chem

57:2996-2997.

*Raabe OG. 1986. Inhalation uptake of selected chemical vapors at trace

levels. Report to California state Air Resources Board, Sacramento. NTIS

PB86-209863.

*Rao GS, Osborn JC, Adatia MR. 1982. Drug-nitrite interactions in human

saliva: effects of food constituents on carcinogenic N-nitrosamine

formation. J Dent Res 61:768-771.

*Reuber MD. 1975, Hepatic vein thrombosis in Buffalo strain female rats

ingesting dimethylnitrosamine. Pathol Europ 10:241-244.

*Rhoades JW, Hosenfeld JM, Taylor JM, et al. 1980. Comparison of analysis of

wastewaters for N-nitrosamines using various detectors. IARC Sci Pub1

31:377-381.

*Ross RD, Morrison J, Rounbehler DP, et al. 1977. N-Nitroso compound

impurities in herbicide formulations. J Agric Food Chem 25:1416-1418.

*Rounbehler DP, Reisch J, Fine DH. 1980. Nitrosamines in new motor-cars. Fd

Cosmet Toxicol 18:147-151.

*RTECS. 1988. Registry of Toxic Effects of Chemical Substances. On-line:

08/05/88. Washington, DC: National Institute for Occupational Safety and

Health.

*Sabljic A. 1987. On the prediction of soil sorption coefficients of

organic pollutants from molecular structure: application of molecular

topology model. Environ. Sci Technol 21:358-366.
109

8. REFERENCES

*Sakai A, Inoue T, Tanimura A. 1984. Formation of Volatile Nitrosamines by

Drug-Nitrite Interactions Under Physiological Conditions. Gann 75:245-252.

*SANSS. 1988. Structure and Nomenclature Search System. On-line: 07/28/88.

Chemical Information System.

*Sawicki E, Belsky T, Friedel RA, et al. 1977. N-nitrosodimethylamine in

ambient air. Analytical method. Health Lab Sci 14:59-63.

*Scanlan RA, Barbour JF, Hotchkiss JH, et al. 1980. N-Nitrosodimethylamine

in beer. Fd Cosmet Toxicol 18:27-30.

*Scanlan RA. 1983. Formation and Occurrence of Nitrosamines in Food. Cancer

Res. (Suppl.) 43:2435s-2440s.

*Scherf HR, Schmahl D. 1975. Experimental investigations on immunodepressive

properties of carcinogenic substances in male Sprague-Dawley

rats. 52:76-87.

*Sen NP, Seaman S. 1981a. Gas liquid chromatographic-thermal energy

analyzer determination of N-nitrosodimethylamine in beer at low parts per

billion level. J Assoc Off Anal Chem 64:933-938.

*Sen NP, Seaman S. 1981b. Possible presence of volatile N-nitrosamines in

cooking oils, margarine and butter. J Agric Food Chem 29:787-789.

*Sen NP, Seaman S, Karpinsky K. 1984. Determination of

N-nitrosodimethylamine in nonfat dry milk: collaborative study. J Assoc Off

Anal Chem 67:232-236.

*Sen NP, Tessier L, Seaman SW, et al. 1985a. Volatile and nonvolatile

nitrosamines in fish and the effect of deliberate nitrosation under

simulated gastric conditions. J Agric Food Chem 33:264-268.

*Sen NP, Kushwaha SC, Seaman SW, et al. 1985b. Nitrosamines in baby bottle

nipples and pacifiers: occurrence, migration and effect of infant formulas

and fruit juices on in vitro formation of nitrosamines under simulated

gastric conditions. J Agric Food Chem 33:428-433.

*Shapley D. 1976. Nitrosamines: scientists on the trail of prime suspect in

urban cancer. Science 191:268-270.

*Sharma RK, Lemmon M, Bakke J, et al. 1983. Studies of in utero sister

chromatid exchange induction and cell replication kinetics [abstract].

Environ Mutagen 5:406.

*Sharma RK, Jacobson-Kram D, Lemmon M et al. 1985. Sister chromatid and

cell replication kinetics in fetal and material cells after treatment with

chemical teratogens. Mutat Res 158:217-231.
110

8. REFERENCES

*Shimizu RW, Sun JD, Li AP, et al. 1984. The use of sister-chromatid

exchange in Chinese hamster primary lung cell cultures to measure

genotoxicity. Mutat Res 130:333-342.

*Singer B. 1979. N-nitroso alkylating agents: formation and persistence of

alkyl derivatives in mammalian as contributing factors in carcinogens. J

Nat1 Cancer Inst 62:1329-1339.

*Sirianni SR, Huang CC. 1987. Comparison of S9 fractions from rats, mice,

and Chinese hamsters to metabolize dimethylnitrosamine and

diethylnitrosamine to intermediates that induce sister-chromatid exchanges

in V79 cells. Mutat Res 188:7-11.

*Skaare JU, Nafstad I. 1978. Interaction of vitamin E and selenium with the

hepatotoxic agent dimethylnitrosamine. Acta Pharmacol Toxicol 43;119-128.

*Song PJ, Hu JF. 1988. N-Nitrosamines in Chinese foods. Fd Chem Toxicol

26:205-208.

*Spiegelhalder B. 1984. Occupational exposure to N-nitrosamines. Air

measurements and biological monitoring. IARC Sci Pub1 57:937-942.

*Spiegelhalder B, Preussmann R. 1984. Contamination of toiletries and

cosmetic products with volatile and nonvolatile N-nitroso carcinogens. J

Cancer Res Clin Oncol 108:160-163.

*Spiegelhalder B, Preussmann R. 1985. In vivo nitrosation of amidopyrine in

humans: use of 'ethanol effect' for biological monitoring of

N-nitrosodimethylamine in urine. Carcinogenesis 6:545-548.

*Spiegelhalder B, Eisenbrand G, Preussmann R. 1979. Contamination of beer

with trace quantities of N-nitrosodimethylamine. Fd Cosmet Toxicol 17:29-31.

*Spiegelhalder B, Eisenbrand G, Preussmann R. 1982. Urinary excretion of

N-nitrosamines in rats and humans. IARC Sci Pub1 41:443-449.

*State of Kentucky. 1986. New or Modified Sources Emitting Toxic Air

Pollution. 401 KAR 63:022.

*Steinmetz KL, Mirsalis JC. 1984. Induction of unscheduled DNA synthesis in

primary cultures of rat pancreatic cells following in vivo and in vitro

treatment with genotoxic agents. Environ Mutagen 6:321-330.

*Strombeck DR, Harrold D, Rogers Q, et al. 1983. Plasma amino acid,

glucagon, and insulin concentrations in dogs with nitrosamine-induced

hepatic disease. Am J Vet Res 44:2028-2036.
111

8. REFERENCES

*Stumpf R, Margison GP, Montesano R, Pegg AE. 1979. Formation and loss of

alkylated purines from DNA of hamster liver after administration of

dimethylnitrosamine. Cancer Res 39:50-54.

*Sumi Y, Miyakawa M. 1983. Susceptibility of germ-free rats to the

hepatotoxic effects of dimethylnitrosamine or dimethylamine plus sodium

nitrite administered orally. Cancer Res 43:2942-2946.

*Swarm RL, Laskowski DA, McCall PJ, et al. 1983. A rapid Method for the

Estimation of the Environmental Parameters Octanol/Water Partition

Coefficient, Soil Sorption Constant, Water to Air Ratio and Water

Solubility. Res Rev 85:17-28.

*Swarm PF. 1984. Effect of ethanol on nitrosamine metabolism and

distribution. Implications for the role of nitrosamines in human cancer and

for the influence of alcohol consumption on cancer incidence. IARC Sci Pub1

57:501-512.

*Swarm PF, Coe AM, Mace R. 1984. Ethanol and dimethylnitrosamine and

diethylnitrosamine metabolism and disposition in the rat. Possible

relevance to the influence of ethanol on human cancer incidence.

Carcinogenesis 5:1337-1343.

*Tabak HH, Quave SA, Mashni CI, et al, 1981A. Biodegradability studies for

predicting the environmental fate of organic priority pollutants. In: Test

protocols for environmental fate and movement of toxicants. Proceedings of

94th annual meeting of symposium association of official Anal Chem,

Washington, DC, 267-327.

*Takayama S, Oota K. 1965. Induction of malignant tumors in various strains

of mice by oral administration of N-nitrosodimethylamine and

N-nitrosodiethylamine. Gann 56:189-199.

*Tate RL III, Alexander M. 1975. Stability of nitrosamines in samples of

lake water, soil, and sewage. J Nat1 Cancer Inst. 54:327-330.

*Tates AD, Neuteboom I, Hofker M., et al. 1980. A micronucleus technique for

detecting clastogenic effects of mutagens/carcinogens (DEN, DMN) in

hepatocytes of rat liver in vivo. Mutat Res 74:11-20.

*Telling GM. 1972. A gas-liquid chromatographic procedure for the detection

of volatile N-nitrosamines at the ten parts per billion level in foodstuffs

after conversion to their corresponding nitramines. J Chromatog 73:79-87.

*Terao K, Aikawa T, Kera K. 1978. A synergistic effect of

nitrosodimethylamine on sterigmatocystin carcinogenesis in rats. Fd Cosmet

Toxicol 16:591-596.
112

8. REFERENCES

*Terracini B, Palestro G, Ramella GM, et al. 1966. Carcinogenicity of

dimethylnitrosamine in Swiss mice. Br J Cancer 20:871-876.

*Terracini B, Magee PN, Barnes JM. 1967. Hepatic pathology in rats on low

dietary levels of dimethylnitrosamine. Br J Cancer 21:559-565.

*Thomas RG. 1982. Volatilization from water. In: Lyman WJ, Reehl WF,

Rosenblatt DH, eds. Handbook of chemical property estimation methods. New

York, NY: McGraw-Hill Book Co., 15-27.

*Thomas P, Fugmann R, Aranyi C, et al. 1985. The effect of

dimethylnitrosamine on host resistance and immunity. Toxicol Appl Pharmacol

77:219-229.

*Thompson HC Jr, Billedeau SM, Miller BJ. 1986. Gas chromatographic thermal

energy analysis method for N-nitrosodibutylamine in latex infant pacifiers:

collaborative study. J Assoc Off Anal Chem 69:504-507.

*Tomkins DJ, Kwok SE, Douglas GR, et al. 1982. Sister chromatid exchange

response of.human diploid fibroblasts and Chinese hamster ovary cells to

dimethylnitrosamine and benzo(a)pyrene. Environ Mutagen 4:203-214.

*Trzos RJ, Petzold GL, Brunden MN, et al. 1978. The evaluation of sixteen

carcinogens in the rat using the micronucleus test. Mutat Res 58:79-86.

*Tuazon EC, Carter WPL, Atkinson R, et al. 1984. Atmospheric reactions of

N-nitrosodimethylamine and dimethylnitramine. Environ Sci Tech 18:49-54.

*Ungar H. 1984. Primary portal venopathy in the golden hamster treated with

low doses of dimethylnitrosamine. Liver 4:244-254.

*Ungar H. 1986. Venoocclusive disease of the liver and phlebectatic

peliosis in the golden hamster exposed to dimethylnitrosamine. Path Res

Pratt 181:180-187.

*Usero JL, Del Arco A, Izquierdo C, et al. 1987. Comparative study of

highperformance

liquid chromatography with ultraviolet detection and gas

chromatography with the Hall electrolytic conductivity detector in the

analysis of N-nitroso compounds. J Chromatog 407:355-362.

VIAR. 1987. Contract Laboratory Program Statistical Database. Output date:

April 13, 1987.

*VIEW Database. 1989. Agency for Toxic Substances and Disease Registry

(ATSDR), Office of External Affairs, Exposure and Disease Registry Branch,

Atlanta, GA. ,June, 1989.
113

8. REFERENCES

*Wade GG, Mandel R, Ryser HJ-P. 1987. Marked synergism of

dimethylnitrosamine carcinogenesis in rats exposed to cadmium. Cancer Res

47:6606-6613.

*Walker EA, Castegnaro M, Garren L, et al. 1978. Limitations to the

protective effect of rubber gloves for handling nitrosamines. IARC Sci Pub1

19:535-543.

*Waynforth HB, Magee PN. 1974. The effect of N-nitroso-N-methylurea and

N-dimethylnitrosamine on cell mediated and humoral immune responses in rats

and mice. Br J Cancer 30:512-523.

*Weast RC, ed. 1983. CRC handbook of chemistry and physics. 64th ed. Boca

Raton, FL: CRC Press, C-270.

*Webb KS, Gough TA, Carrick A, et al. 1979. Mass spectrometric and

chemiluminescent detection of picogram amounts of N-nitrosodimethylamine.

Anal Chem 51;989-992.

*Weston RJ. 1984. Analysis of cereals, malted foods and dried legumes for

N-nitrosodimethylamine. J Sci Food Agric 35:782-786.

*Wild CP, Lu SH, Montesano R. 1987. Radioimmunoassay used to detect DNA

alkylation adducts in tissues from populations at high risk for oesophageal

and stomach cancer. Iarc Sci Pub1 84:534-537.

*Windholz M, ed. 1983. The Merck index. 10th ed. Rahway, NJ: Merck and Co.,

Inc., 952, 864, 1387-1388.

*Wishnok JS, Rogers AE, Sanchez 0, et al. 1978. Dietary effects on the

pharmacokinetics of three carcinogenic nitrosamines. Toxicol Appl Pharmacol

43:391-398.

*Wyrobek AJ, Bruce WR. 1975. Chemical induction of sperm abnormalities in

mice. Proc Nat Acad Sci. 72:4425-4429.

*Xesarone CF, Bolognesi C, Santi L. 1979. DNA repair synthesis in mice

spermatids after treatment with N-methyl-N-nitroso-urea and Ndimethylnitrosamine:

preliminary results. Toxicology 12:183-186.

*Yamane Y, Sakai K, Umeda T, et al. 1984. Suppressive effect of cupric

acetate on DNA alkylation, DNA synthesis and tumorigenesis in the liver of

dimethylnitrosamine-treated rats. Gann 75:1062-1069.

*Yoo J-SH, Guengerich FP, Yang CS. 1988. Metabolism of

N-nitrosodialkylamines by human liver microsomes. Cancer Res 88:1499-1505.

*Yu MC, Henderson BE. 1987. Intake of Cantonese-style salted fish as a

cause of nasopharyngeal carcinoma. IARC Sci Pub1 84:547-549.
114

8. REFERENCES

*Zeisel SH, daCosta KA, LaMont JT. 1988. Mono-, di- and trimethylamine in

human gastric fluid: Potential substrates for nitrosodimethylamine

formation. Carcinogenesis 9:179-181.

*Zoeteman BCJ, Harmsen K, Linders JBHJ, et al. 1980. Persistent organic

pollutants in river water and ground water of The Netherlands. Chemosphere

9:231-249.
115

9. GLOSSARY

Acute Exposure -- Exposure to a chemical for a duration of 14 days or less,

as specified in the Toxicological Profiles.

Adsorption Coefficient (KOC) -- The ratio of the amount of a chemical

adsorbed per unit weight of organic carbon in the soil or sediment to the

concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or

soil (i.e., the solid phase) divided by the amount of chemical in the

solution phase, which is in equilibrium with the solid phase, at a fixed

solid/solution ratio. It is generally expressed in micrograms of chemical

sorbed per gram of soil or sediment.

Bioconcentration Factor (BCF) -- The quotient of the concentration of a

chemical in aquatic organisms at a specific time or during a discrete time

period of exposure divided by the concentration in the surrounding water at

the same time or during the same time period.

Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or

group of studies which produces significant increases in incidence of

cancer (or tumors) between the exposed populaton and its appropriate

control.

Carcinogen -- A chemical capable of inducing cancer.

Ceiling Value (CL) -- A concentration of a substance that should not be

exceeded, even instantaneously.

Chronic Exposure -- Exposure to a chemical for 365 days or more, as

specified in the Toxicological Profiles.

Developmental Toxicity -- The occurrence of adverse effects on the

developing organism that may result from exposure to a chemical prior to

conception (either parent), during prenatal development, or postnatally to

the time of sexual maturation. Adverse developmental effects may be detected

at any point in the life span of the organism.

Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a

result of prenatal exposure to a chemical; the distinguishing feature

between the two terms is the stage of development during which the insult

occurred. The terms, as used here, include malformations and variations,

altered growth, and in utero death.

EPA Health Advisory -- An estimate of acceptable drinking water levels for a

chemical substance based on health effects information. A health advisory is

not a legally enforceable federal standard, but serves as technical guidance

to assist federal, state, and local officials.
116

9. GLOSSARY

Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental

concentration of a contaminant from which one could escape within 30 min

without any escape-impairing symptoms or irreversible health effects.

Intermediate Exposure -- Exposure to a chemical for a duration of 15-364

days, as specified in the Toxicological Profiles.

Immunologic Toxicity -- The occurrence of adverse effects on the immune

system that may result from exposure to environmental agents such as

chemicals.

In vitro -- Isolated from the living organism and artificially maintained,

as in a test tube.

In vivo -- Occurring within the living organism.

Lethal Concentration(LO) (LCLO) -- The lowest concentration of a chemical in

air which has been reported to have caused death in humans or animals.

Lethal Concentration(50) (LC50) -- A calculated concentration of a chemical

in air to which exposure for a specific length of time is expected to cause

death in 50% of a defined experimental animal

population.

Lethal Dose(LO) (LDLO)-- The lowest dose of a chemical introduced by a

route other than inhalation that is expected to have caused death in humans

or animals.

Lethal Dose(50) (LD50) -- The dose of a chemical which has been calculated

to cause death in 50% of a defined experimental animal population.

Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical

in a study or group of studies which produces statistically or biologically

significant increases in frequency or severity of adverse effects between

the exposed population and its appropriate control.

LT50 (lethal time) -- A calculated period of time within which a specific

ccncentration of a chemical is expected to cause death in 50% of a defined

experimental animal population.

Malformations -- Permanent structural changes that may adversely affect

survival, development, or function.

Minimal Risk Level -- An estimate of daily human exposure to a chemical

that is likely to be without an appreciable risk of deleterious effects

(noncancerous) over a specified duration of exposure.
117

9. GLOSSARY

Mutagen -- A substance that causes mutations. A mutation is a change in the

genetic material in a body cell, Mutations can lead to birth defects,

miscarriages, or cancer.

Neurotoxicity -- The occurrence of adverse effects on the nervous system

following exposure to a chemical.

No-Observed-Adverse-Effect Level (NOAEL) -- That dose of chemical at which

there are no statistically or biologically significant increases in

frequency or severity of adverse effects seen between the exposed

population and its appropriate control. Effects may be produced at this

dose, but they are not considered to be adverse.

Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of the

concentrations of a chemical in n-octanol and water, in dilute solution.

Permissible Exposure Limit (PEL) -- An allowable exposure level in

workplace air averaged over an 8-h shift.

q1* -- The upper-bound estimate of the low-dose slope of the dose-response

curve as determined by the multistage procedure. The ql* can be used to

calculate an estimate of carcinogenic potency, the incremental excess cancer

risk per unit of exposure (usually g/L for water, mg/kg/day for food, and

g/m3

 for air).

Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an

order of magnitude) of the daily exposure of the human population to a

potential hazard that is likely to be without risk of deleterious effects

during a lifetime. The RFD is operationally derived from the NOAEL (from

animal and human studies) by a consistent application of uncertainty factors

that reflect various types of data used to estimate RfDs and an additional

modifying factor, which is based on a professional judgment of the entire

database on the chemical. The RfDs are not applicable to nonthreshold

effects such as cancer.

Reportable Quantity (RQ) -- The quantity of a hazardous substance that is

considered reportable under CERCLA. Reportable quantities are: (1) 1 lb or

greater or (2) for selected substances, an amount established by regulation

either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities

are measured over a 24-h period.

Reproductive Toxicity -- The occurrence of adverse effects on the

reproductive system that may result from exposure to a chemical. The

toxicity may be directed to the reproductive organs and/or the related

endocrine system. The manifestation of such toxicity may be noted as

alterations in sexual behavior, fertility, pregnancy outcomes, or

modifications in other functions that are dependent on the integrity of this

system.
118

9. GLOSSARY

Short-Term Exposure Limit (STEL) -- The maximum concentration to which

workers can be exposed for up to 15 min continually. No more than four

excursions are allowed per day, and there must be at least 60 min between

exposure periods. The daily TLV-TWA may not be exceeded.

Target Organ Toxicity -- This term covers a broad range of adverse effects

on target organs or physiological systems (e.g., renal, cardiovascular)

extending from those arising through a single limited exposure to those

assumed over a lifetime of exposure to a chemical.

TD50 (toxic dose) -- A calculated dose of a chemical, introduced by a route

other than inhalation, which is expected to cause a specific toxic effect in

50% of a defined experimental animal population.

Teratogen -- A chemical that causes structural defects that affect the

development of an organism.

Threshold Limit Value (TLV) -- A concentration of a substance to which most

workers can be exposed without adverse effect. The TLV may be expressed as a

TWA, as a STEL, or as a CL.

Time-weighted Average (TWA) -- An allowable exposure concentration averaged

over a normal 8-h workday or 40-h workweek.

Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD

from experimental data. UFs are intended to account for (1) the variation in

sensitivity among the members of the human population, (2) the uncertainty

in extrapolating animal data to the case of humans, (3) the uncertainty in

extrapolating from data obtained in a study that is of less than lifetime

exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL

data. Usually each of these factors is set equal to 10.
119

APPENDIX: PEER REVIEW

A peer review panel was assembled for N-nitrosodimethylamine. The

panel consisted of the following members: Dr. Russell Cattley, Department

of Microbiology, Pathology and Parasitology, College of Veterinary Medicine,

North Carolina State University; Dr. Elaine Faustman, Department of

Environmental Health, University of Washington; Dr. James Felton, Molecular

Biology Section, Lawrence Livermore National Laboratory, University of

California; Dr. Freddy Homburger, Bio-Research Consultants, Inc; and Dr.

Raymond Smith, Department of Pathology and Microbiology, University of

Nebraska Medical Center. These experts collectively have knowledge of Nnitrosodimethylamine's physical and-chemical properties, toxicokinetics, key

health end points, mechanisms of action, human and animal exposure, and

quantification of risk to humans. All reviewers were selected in conformity

with the conditions for peer review specified in the Superfund Amendments

and Reauthorization Act of 1986, Section 110.

A joint panel of scientists from ATSDR and EPA has reviewed the peer

reviewers' comments and determined which comments will be included in the

profile. A listing of the peer reviewers' comments not incorporated in the

profile, with a brief explanation of the rationale for their exclusion,

exists as part ,of the administrative record for this compound. A list of

databases reviewed and a list of unpublished documents cited are also

included in the administrative record.

The citation of the peer review panel should not be understood to

imply their approval of the profile's final content. The responsibility for

the content of this profile lies with the Agency for Toxic Substances and

Disease Registry.

U.S. GOVERNMENT PRINTING OFFICE: 1991-535-152/