Worker Health Study Summaries

Research on long-term exposure

Navy Cable Manufacturers (Chlorinated Naphthalenes Exposure)

1996

Study Background

NIOSH studied navy cable manufacturers for exposure to look at the long-term effects of exposure to chlorinated naphthalenes (CNs). The purpose of the study was to see if exposure to CNs causes cirrhosis of the liver or the cancers soft tissue sarcoma STS), lymphoma, or liver cancer.

Questions and Answers

Why Didn’t You Give Us This Information 50 Years Ago?

Although the exposures we studied happened during World War II, NIOSH didn’t begin this study until 1982. We only completed the study in 1994. We could not provide the study results until the study was done.

How Could I Have Been in a Study Without Knowing It?

Because the study was based on records – we didn’t need to contact workers. The study was based on work records and death certificates.

When Were the Effects of CNs First Known?

Doctors have known since World War I that chlorinated naphthalenes CNs) can cause the acne-like skin disease chloracne. Chloracne is a severe land of acne that results only from certain types of chemical exposures. In the late 1930’s, doctors began to suspect that CNs could cause immediate harm to the liver and even death. This was because a number of people exposed to CNs died from acute yellow atrophy of the liver. This is a severe type of liver damage. During this time, studies on lab animals also showed that CNs damaged the liver. However, the NIOSH study is the first one to look at long-term effects. Until it was completed, we didn’t know that CNs could cause cirrhosis of the liver years after exposure ended.

What Do You Mean by “Long-Term Effects?”

When a chemical causes illness right away, it is said to have short-term or acute effects. For example, a very high exposure to carbon monoxide in an enclosed space (like a car running in a closed garage) can cause death very quickly. When CNs were first used, high exposures caused chloracne and acute yellow atrophy of the liver to develop very quickly. Sometimes chemicals don’t cause immediate illness. An illness might not show up until years later. Years of exposure may be required. This is called a long-term or chronic effect. An example is cigarette smoking and lung cancer. It can take decades of smoking before the lung cancer appears. Really, it’s been slowly developing all that time. Diseases that develop over a long time are said to have a long latency period.

Where Do CNs Fit into This?

Before the NIOSH study, we knew that high exposures to CNs could cause immediate liver disease, but we didn’t know if lower exposures could cause liver disease years after exposure. Our study has now suggested that they can. Not every exposed person gets sick, though. Whether you get sick depends on the dose you received, your exposure to other harmful substances, hereditary sfactors, and your general health.

What Do “Exposure” and “Dose” Mean?

Exposure means that a chemical or physical agent could be taken into or affect your body. For example, when you lie on a beach, you are exposed to the sun (a physical agent), which can cause sunburn. When you work in a factory with chemicals, you could be exposed to the chemicals. The amount of chemicals that get into your body is called the dose. The dose is a combination of the concentration of the chemical and the length of time that you are exposed to it.

Dose-Response

For most diseases, the higher the dose, the more likely you will become sick. This association between dose and sickness is called the dose-response relationship. In our study, we didn’t know the concentration of Halowax in the air. We didn’t even know where in the plant people worked. Therefore, our best estimate of exposure and dose was how long each person had worked in the plant. However, length of employment is not a very good estimate of exposure or dose, and sometimes a workplace chemical causes disease without showing an association with length of employment.

Rectal Cancer

In our study, we did see a relationship between length of employment and rectal cancer. This was confusing, however, because no chemicals known to cause rectal cancer were present. Therefore, we cannot tell if the rectal cancer was related to work.

Cirrhosis of the Liver

On the other hand, even though there is good evidence that CNs can cause deaths from liver disease, we did not see a clear link between death from cirrhosis of the liver and length of employment. This probably was due to the limitations of using length of employment as a measure of dose. Since we had to count workers with little exposure to Halowax the same as those with a lot of exposure, this might have kept us from seeing a clear dose-response relationship with cirrhosis. In addition, most workers were exposed to Halowax for less than 2 years. It is difficult to see a dose-response relationship with such short exposures.

Chlorination

Another factor that is important with chlorinated naphthalenes is the number of chlorine atoms on the naphthalene molecule. A naphthalene molecule could have anywhere from 1 to 8 atoms of chlorine on it. (The number of chlorine atoms describes the degree of chlorination of the naphthalene). Usually, the more chlorine atoms, the more toxic the chlorinated naphthalene is.

How Do Chemicals Get into Our Bodies?

The 3 routes of exposure are: eating, breathing, and through the skin.

Eating

Eating is a less common route in the workplace, but can happen if it’s dirty where people eat, if they can’t wash their hands, or if they smoke with dirty hands.

Breathing

Breathing chemicals in the air is a common route of exposure at work. These chemicals often affect the lungs, but could get to other organs in the body, too. Heating the wax-like Halowax lets off vapors in the air that can be breathed in. Breathing was probably the most important route of exposure for Halowax. We think that Halowax was in the air throughout the factory, not just in the Asbestos Department.

Skin

Some chemicals can be absorbed through the skin. Halowax is one of them. These chemicals can affect various organs in the body, not just the skin. The skin disease chloracne is usually caused by skin contact, but also can be caused by breathing CNs.

Why Do CNs Affect the Liver?

The liver is the body’s chemical factory. One of the functions of the liver is to get rid of the poisons or toxins that get in our bodies. The liver performs chemical reactions that change the chemicals so we can excrete them. Since harmful chemicals are processed by the liver, they sometimes hurt the liver itself. Alcohol is the best-known substance that harms the liver, but there are many more as well. Although CNs are quite different from alcohol, the effect of CNs is also mainly on the liver.

What Is Cirrhosis of the Liver?

It is the last stage of chronic liver disease. It consists of widespread fibrosis or scarring and the death of liver cells. It usually happens over the course of several years.

Can You Tell What Caused Someone’s Cirrhosis?

This sometimes can be difficult. Late stage cirrhosis of the liver tends to look the same whatever caused it. Also, like many occupational diseases, cirrhosis from CNs can develop years after exposure. With that type of delay, it is hard to connect the disease to the exposure. A doctor would look at a patient’s history of exposures to liver poisons to try to determine the cause. Sometimes, there could be a combination of causes, such as both alcohol and CNs. Since there is research evidence from both humans and animals that CNs cause cirrhosis of the liver, potential exposure to CNs (even years ago) would certainly suggest that they played an important role. Doctors who specialize in diseases caused at work (occupational medicine) are trained to make these evaluations. You may want to see a doctor at one of the clinics listed on the green sheet, if one is near you.

How Can I Avoid Getting Cirrhosis?

The first thing to do is to see your doctor. Tell him or her that you were exposed to CNs 50 years ago, and that you may still be at increased risk of developing cirrhosis of the liver. Your doctor will probably do some tests to see if your liver is functioning properly. He or she will then advise you based on the results. These tests may be slightly abnormal even though you do not feel any symptoms. Even if the tests show that your liver has some problems, that does not necessarily mean that they will become serious. Not everyone exposed to CNs will develop liver disease. 150 people out of the 9,028 in our study died of cirrhosis of the liver during our study. We’re not sure why these people were affected. Perhaps their exposures to CNs were higher. Maybe they drank more alcohol or were exposed to other liver poisons. Possibly hereditary factors made them more susceptible.

Should I Avoid Other Liver Poisons?

Yes. Even though your liver is healthy today, it’s best to avoid other substances that harm the liver. Your liver may have survived the CNs just fine, but a “double whammy” from another chemical that also hurts the liver could be too much.

Avoid Alcohol

Discuss with your doctor whether you should restrict your consumption of alcohol.

Avoid Certain Medications

Some medications harm the liver, even over-the-counter ones. Ask your doctor about the ones you take.

Avoid Harmful Chemicals

Many other chemicals used at work, around the home, or in hobbies could hurt the liver. Examples include furniture strippers, solvents, weed killers, and pesticides. Ask your doctor or NIOSH about the chemicals that you use. Some chemicals might be used safely with the proper protection. Protective gloves and clothing could prevent skin contact. Respirators can prevent breathing chemicals. Call NIOSH for advice on protection because the clothing and respirators must be right for the specific substance that you are using or they won’t help.

How Concerned Should I Be?

You should be concerned, but not anxious. Most people will not develop liver problems, and that’s true for you, too. The best thing is to talk to your doctor, so you know for sure. If you have other questions, call at the NIOSH toll-free number: 800-356-4674.

How the NIOSH Halowax Study was done

This plant made asbestos-insulated cable for the Navy during World War II. Halowax was the trade name of the CN used to insulate the electrical cable in the Asbestos Department. In addition to Halowax, other possible toxic exposures included asbestos, carbon tetrachloride, and polychlorinated biphenyl (PCBs).

Subjects

The study group included 9,028 men and women who were employed from 1940 through 1944. We weren’t able to find out which departments people worked in. Therefore, our study group included workers who never worked in the Asbestos Department, as well as those who did.

Records

The study was based entirely on records. Workers were not medically examined. They did not know they were included in the study. We first looked at the death rates for the whole U.S. population. This gave us the expected number of deaths. Then we compared this to the death rates of workers at the study plant.

What the Study Found

Cirrhosis of the Liver

The most important and striking finding was an increase in deaths from cirrhosis of the liver. We expected about 81 deaths, but found 150. This is 1½ to 2 times greater than expected. Most of the deaths (131) were in men. We don’t know why men were more affected than women. Unfortunately, deaths from cirrhosis have continued into recent years.

Cirrhosis of the liver is the liver disease usually associated with alcoholism. According to the death certificates, 59 of the deaths were related to alcoholism. 83 of the cirrhosis deaths were not. It’s possible that drinking and Halowax exposure together caused some of the cirrhosis of the liver. However, Halowax by itself also appeared to cause cirrhosis of the liver.

Soft Tissue Sarcoma (STS)

STS is a catch-all term for cancers in soft tissues of the body. We found some association between Halowax and deaths from STSs, but the findings were not as clear as those for cirrhosis. We expected about 3 deaths from STS, and found 5. Four of them were in men.

Lung Cancer

A small increase in death from lung cancer was seen (303 deaths seen, about 231 expected). There are two likely explanations. First, this may have been related to the asbestos used to insulate the cable. However, it doesn’t appear that most workers had heavy asbestos exposure because we did not see the pattern of disease typically seen with heavy asbestos exposure. Second, smoking may have caused the lung cancer.

Liver Cancer

Because CNs affect the liver, we were concerned about liver cancer before the study. We found a small increase in deaths from liver cancer (23 seen, about 18 expected). However, we could not determine whether there was a link to Halowax.

Lymphoma

One of the cancers we were concerned about before the study was lymphoma. How- ever, we did not find a link between Halowax and deaths from lymphoma.

Oral Cancer

We were surprised to find an elevation of cancers inside the mouth and throat in our study. This hadn’t been seen in other studies, so we had not expected it. This elevation in oral cancers only occurred in men, not women. Among men, we expected about 21 deaths from oral cancer, but we found 39. We don’t know why men had this increase or whether it was due to work. The main risk factors for these cancers are the use of snuff or chewing tobacco, smoking, and drinking. These behaviors may have played a role.

Rectal Cancer

We were also surprised to find an increase in cancer of the rectum. We expected about 28 deaths, but we found 58. We don’t know for sure if this excess was associated with work, but there was some evidence that it was linked to how long people had worked.

What Does This Mean for You?

It is important for you to understand the results of this study and to discuss them with your doctor. Even though we found some increased risks, that doesn’t mean that you will get cirrhosis of the liver or cancer. There are steps you can take today to protect your health. The blue sheet lists these. The most important ones are:

1. to discuss your Halowax exposure with your doctor,
2. to discuss with your doctor whether to reduce or stop drinking, and
3. not to smoke or use snuff or chewing tobacco.

Any Questions?

If you have any questions about this study or want a copy of the technical reports, call the NIOSH toll-free number: 800-356-4674.

Steps to Protect Your Health

Talk to Your Doctor

Tell your doctor that you were exposed 50 years ago to chlorinated naphthalenes. You and your doctor can watch for signs of liver problems.

Talk to your doctor about screening tests for cancer of the rectum. Everyone over age 50 is advised to have a digital rectal exam and a stool slide test every year and a sigmoidoscopy every 3 to 5 years. These tests screen for colon and rectal cancer.

Alcohol

If you drink alcoholic beverages, discuss with your doctor whether you should reduce the amount or quit. This is because of your exposure to Halowax, even though it was long ago. It’s possible that Halowax and alcohol together could increase your risk of cirrhosis of the liver.

Other Liver Poisons

Avoid exposure to chemicals or drugs that could hurt your liver. The chemicals and drugs that damage the liver are too numerous to name here. Ask your doctor about any medications that you take (even over-the-counter).

Before using solvents, furniture strippers, weed killers, bug killers, or other chemicals, call your doctor or NIOSH to find out if they harm the liver. Avoid breathing and skin contact with chemicals. Call NIOSH for advice on protective gloves, clothing, and respirators.

Tobacco Products

If you smoke or use smokeless tobacco products, NIOSH recommends that you quit. Smoking causes lung cancer, especially in people exposed to asbestos. It also causes heart disease and oral cancer. Snuff and chewing tobacco cause oral cancer.

Even if you have smoked or used smokeless tobacco for a long time, stopping now will improve your health. The back of this sheet lists information on programs to quit.

See Your Dentist

Ask your dentist to check your mouth for signs of cancer at your regular check-up.

Sources of Information

If you have any questions about any information in this packet, call the NIOSH toll-free number: 800-356-4674.

Information on Tobacco Use

The American Cancer Society has pamphlets on stopping tobacco use and classes on quitting smoking. Call their toll-free number, 800-227-2345, which will connect you with an ACS office in your State.

The American Lung Association also has pamphlets and classes on quitting smoking. Call their toll-free number, 800-232-5864, which will connect you with an ALA office in your State.

Technical Information for Your Doctor

NIOSH completed a study of the long-term effects of exposure to chlorinated naphthalenes (CNs)

The study plant used CNs (sold under the trade name Halowax) to insulate electrical cable from 1939 to 1944. Chlorinated naphthalenes consist of 2 fused aromatic rings with 1 to 8 of the hydrogens substituted with chlorine.

The major study finding was that workers exposed to the chlorinated naphthalene product Halowax during World War II have an increased risk of dying from cirrhosis of the liver that continues today. Certain cancers were also elevated.

Exposure to Other Hepatotoxins

Although it has not been shown that exposure to other hepatotoxins in conjunction with Halowax increases the risk of cirrhosis in humans, consider advising your patient to reduce his or her consumption of alcohol and caution your patient about exposure to other hepatotoxic chemicals and Pharmaceuticals. Chlorinated naphthalenes are wax-like substances that have been used in cable, insulation, wood preservatives, capacitors, engine oils, and cutting and grinding fluids. In the US, production of CNs steadily declined after World War II, and ceased in 1980.

At the study site, CNs were melted in open vats through which wires coated with asbestos were drawn. It appears that CN vapor exposure was widespread throughout the plant. Vapor from the impregnating vats blown out the stacks may have drifted back into the plant, particularly on the west side. Chlorinated biphenyls and carbon tetrachloride were also present, but it is not possible to document how extensive worker exposure may have been to these compounds. Most of the cohort members did not continue employment after WWII ended. Maximum exposure to Halowax was 5 years, and over 80% of the workers were exposed for less than 2 years.

A Priori Hypotheses

NIOSH initiated this study because of the toxicologic similarity of CNs to chlorinated dibenzodioxins and polychlorinated biphenyls PCBs). We hypothesized that CN exposure might be associated with an increased risk of soft tissue sarcoma, lymphoma, liver cancer, and cirrhosis of the liver.

Methods

The mortality experience of workers was compared to that expected based on US and Westchester County death rates. The underlying cause of death was taken from death certificates.

Study Group

The study cohort included 9,028 men and women employed from 1940 – 1944. Of the 9,028, a subcohort of 460 workers who had had chloracne was also identified. Records do not exist to identify which departments employees worked in or to determine their exposure levels.

Study Results for Chloracne

Use of CNs during World War I led to the first large outbreaks of chloracne. Chloracne is an acne-like disorder with comedone formation with or without cysts or pustules, with the follicular orifices filed with sebaceous and keratinous material. Outbreaks of chloracne from CN vapor exposure occurred in the late 1930s and 1940s. 460 cases occurred among workers in the NIOSH study.

There was no substantial difference in death rates between the workers who had chloracne and those who did not.

Study Results for Cancer

A non significant elevation in liver cancer was seen in the total cohort (23 deaths seen, 18 expected), with no elevation among the chloracne subcohort. The investigators concluded that the study results were inconclusive for liver cancer. No association between CNs and cancer of lymphatic and hematopoietic tissue was found (56 deaths seen, 75 expected).

It is difficult to assess soft tissue sarcomas in a mortality study such as this one. The investigators concluded that the data were suggestive of an association, but did not conclusively demonstrate one. No excess was observed among women (1 death), but 4 deaths were seen among men, where 2.25 were expected. One of the male deaths was in the chloracne subcohort, where only 0.21 deaths were expected. Neither the male nor the chloracne elevations in risk were statistically significant.

We found elevations in 3 cancers not hypothesized to be elevated: lung, oral, and rectal cancers. There was a small increase in death from lung cancer (303 seen, 231 expected). This could have been related to smoking or to the asbestos used to insulate the cable. However, we did not see the pattern of diseases typically seen among people heavily exposed to asbestos (no excess of asbestosis and only 1 case of mesothelioma), so it does not appear that most workers were heavily exposed to asbestos.

Oral cancer was only elevated in males (39 seen, 21 expected) and may have been associated with non-occupational risk factors smokeless tobacco, smoking, and alcohol). Rectal cancer was elevated in both males and females (58 seen, 28 expected). Whether this excess had an occupational or non-occupational etiology is not clear.

Study Results for Cirrhosis of the Liver

A number of deaths from acute yellow atrophy of the liver (including 8 at the study plant) were reported in the 1930s and 1940s following exposure to CN vapor over several weeks to months, with post-mortem liver changes of widespread degeneration and necrosis. Hepatotoxicity from CN exposure has also been well documented in animal studies, with a histological pattern of fatty infiltration, centrilobular degeneration, necrosis, nd cirrhosis. No long-term studies have been done of liver function among groups of workers exposed to CNs.

The most striking finding of the study was a significant increase in mortality from cirrhosis of the liver (150 deaths seen, 81 expected). Excess mortality was more pronounced in males n=131) than females, but was not higher in the chloracne subcohort than in the total cohort.

According to death certificates, mortality was significantly elevated for both “cirrhosis of the liver with mention of alcohol” and for “cirrhosis of the liver without mention of alcohol.” Deaths from alcoholic cirrhosis peaked in individuals aged 60+ at death. Deaths from non-alcoholic cirrhosis peaked in the 40-49 year old age group. Deaths from cirrhosis have continued into the most recent years of follow-up.

Recommendations for Evaluation, Treatment, and Screening

Suggested Evaluation, Treatment, and Screening

Liver function test (ALT, AST, or GTP). If normal, repeat periodically.

If serum transaminase levels are persistently elevated, review patient’s medical and occupational history, consider additional tests of liver function, and consider referral to a liver specialist or consultation with an occupational medicine specialist.

Annual digital rectal exam and hemoccult, sigmoidoscopy every 3-5 years, and annual dental exam.

Liver Function Tests

Although we do not know the extent of your patient’s exposure to Halowax, the people in the NIOSH study cohort as a group have an elevated risk for cirrhosis of the liver. Therefore, we suggest that he or she be offered a liver function test.

• Serum transaminase levels are the most sensitive, most commonly available tests for hepatic dysfunction. It does not matter if the ALT, AST, or GTP is measured, as there is probably no difference in the sensitivity or specificity or these tests in the diagnosis of hepatotoxicity from chemical exposure. However, all of these tests are nonspecific, and an elevated result does not necessarily indicate liver disease from CN exposure.
• If no abnormality is found in serum transaminase levels, we recommend repeat testing at regular intervals.

It is not known whether avoiding the ingestion of alcoholic beverages reduces the risk of developing cirrhosis related to previous CN exposure, but it may be prudent to caution your patient to minimize alcohol consumption on this basis. Additional Evaluation If a persistently elevated serumtransaminase level is found, additional evaluation should proceed to determine the cause. The work-up should include:

• A review of the patient’s medical history to determine if other risk factors for liver disease are present. These include the use of certain hepatotoxic medications, viral infections, and the use of alcohol. Consider advising a patient with abnormal findings who drinks alcoholic beverages to quit.
• A review of the individual’s occupational history for exposure to other potentially hepatotoxic chemicals. See Table 1.
• Additional tests of liver function, including alkaline phosphatase, bilirubin, lactate dehydrogenase, and protime; and diagnostic aids such as ultrasound, radionuclide scan, computerized axial tomography, or magnetic resonance imaging.
• Possible referral to a specialist in liver diseases for consideration of a liver biopsy. A liver biopsy may be helpful in determining the histology of the liver disease and may help guide potential treatment.
• Possible consultation with an occupational medicine specialist. The Association of Occupational and Environmental Clinics (phone 202-347-4976) maintains a roster of member clinics around the country with specialists who may be helpful. Each worker was sent a list of these clinics.

Cancer Screening

Encourage your patient to have a digital rectal examination and hemocult annually, a sigmoidoscopy every 3 to 5 years, and an annual dental examination.

Any Questions?

If you have any questions about the study, wish to obtain a copy of the technical reports, or want to speak to an occupational physician at NIOSH, contact NIOSH toll-free number: 800-356-4674.

References

Brinkman UA, Reymer HGM (1976): Polychlorinated naphthalenes. J Chromatography 127:203-243.

Collier E, Glasg MB (1943): Poisoning by chlorinated naphthalene. Lancet 244:72 74.

Cotter LH (1944): Pentachlorinated naphthalenes in industry. JAMA 125:273-274.

Drinker CK (1937): Further observations on the possible systemic toxicity of certain of the chlorinated hydrocarbons with suggestions for permissable concentrations in the air of workrooms. J Ind Hyg Tox 21:155-159.

Flinn FB, Jarvik NE (1936): Action of certain chlorinated naphthalenes on the liver. Proc Soc Exp Biol Med 35:118-120.

Greenburg L, Mayers MR, Smith AR (1939): The systemic effects resulting from exposure to certain chlorinated hydrocarbons. J Ind Hyg Tox 21:29-38.

Kleinfeld M, Messite J, Swencicki R (1972): Clinical effects of chlorinated naphthalene exposure. J Occ Med 14:377-379.

Strauss N (1944): Hepato-toxic effects following occupational exposure to Halowax (chlorinated hydrocarbons). Rev of Gastroenterology 11:381-396.

Von Wedel H, Holla WA, Denton J (1943): Observations on the toxic effects resulting from exposure to chlorinated naphthalene and chlorinated phenyls with suggestions for prevention. The Rubber Age 53:419-426.

Ward EM, Ruder AM, Suruda A, et al. (1994a): Acute and chronic liver toxicity resulting from exposure to chlorinated naphthalenes at a cable manufacturing plant during World War II. (In press).

Ward EM, Ruder AM, Suruda A, et al. (1994b): Cancer mortality patterns among female and male workers employed in a cable manufacturing plant during World War II. J Occ Med 36:860-866.

Table 1: Chemical Agents Associated with Occupational Liver Disease

Compound	Type of Injury	Occupation or Use
Arsenic	Grrhosis, hepatocellular carcinoma, angiosarcoma	Pesticides
Beryllium	Granulomatous disease	Ceramics workers
Carbon tetrachloride	Acute hepatocellular injury, cirrhosis	Dry cleaning
Dimethylformamide	Acute hepatocellular injury	Solvent, chemical manufacturing
Dimethylnitrosamine	Hepatocellular carcinoma	Rocket manufacturing
Dioxin	Porphyrea cutanea tarda	Pesticides
Halothane	Acute hepatocellular injury	Anesthesiology
Hydrazine	Steatosis	Rocket manufacturing
Methlene	dianiline Cholestasis	MDA production workers
2-nitropropane	Acute hepatocellular injury	Painters
Phosphorus	Acute hepatocellular injury	Munitions workers
Polychlorinated biphenyls	Subacute liver injury	Production, electrical utility
Tetrachloroethane	Acute or subacute hepatocellular injury	Aircraft manufacturing
Trichloroethylene	Acute hepatocellular injury	Cleaning solvent sniffing
Trinitrotoluene	Acute or subacute hepatocellular injury	Munitions workers
Vinyl chloride	Angiosarcoma	Rubber workers

From: Harrison RJ (1990): Liver Toxicology. In: LaDou J, ed. Occupational Medicine. East Norwalk: Appleton and Lange, pp 247-258.

Additional Resources

Ward E, Ruder A, Suruda A et al. (1994). Cancer mortality patterns among female and male workers employed in a cable manufacturing plant during World War II. Journal of Occupational Medicine 36 (8): 860-866. (Study Report)