Environmental Health Perspectives Volume 107, Number 7, July 1999
The article "Scents & Sensitivity" [EHP 106:A594-A599 (1998)] provides a good summary of the issues involved in concerns and controversies over fragranced products. However, several points should be addressed.
The health effects of fragrances are a general health issue, an indoor air quality issue, an access issue, and an environmental issue. Unfortunately, the only issue the fragrance industry has addressed is that of skin safety for the user of the products. This leaves many areas of concern.
Allergic disease affects 20% of the population and is the sixth leading cause of chronic disease. There are an estimated 17 million asthmatics, and migraine headaches affect as many as 25 million people in the United States. Individuals with nonallergic rhinitis, chronic respiratory disease, and chemical sensitivities should also be included in these numbers. Fragrances are known to trigger and exacerbate all of these conditions. The impact of fragrances on health is a general health issue.
Fragrance chemicals are volatile by nature. This means some of each fragranced product used ends up in the air. The result is complex mixture of chemicals that is constantly changing. Fragrance chemicals are often air, heat, and light sensitive. Very often the compounds that result from the reactions and breakdown that occurs in the air are more irritating than the original compounds. In indoor environments where air exchange is poor, the problems are compounded.
Fragrance chemicals are not removed from wastewater by present sewage treatment methods. Synthetic musk compounds are being found in waterways and in aquatic wildlife. The implications are not known because so little research has been done in the area of fragrance chemical safety. These materials are now in the food chain.
The main focus of safety testing in the fragrance industry has been adverse skin effects. Fragrance materials penetrate the skin, are absorbed into the bloodstream, and are distributed to other organs. Other routes of exposure, such as respiratory and neurologic exposure via olfactory pathways, have been ignored. Ingestion is another route of exposure because many of the same materials are used as flavors in foods.
There are legitimate concerns about the scope and effectiveness of safety testing by the fragrance industry. In the late 1970s it was found that acetylethyltetramethyltetralin (AETT) caused the internal organs of laboratory animals to turn blue. This substance was also severely neurotoxic. Testing by the industry had not pinpointed these side effects, which were discovered by accident after the material had been used in products for over 20 years (1,2).
Musk ambrette was also used in fragrances for years. Testing by the Research Institute for Fragrance Materials indicated that it was safe for use. It was later determined that musk ambrette caused photosensitivity reactions and had neurotoxic properties (3). The International Fragrance Association recommended in 1985 that musk ambrette not be used in products with skin contact. In 1991, musk ambrette was still being found in products tested by the Food and Drug Administration (FDA).
More recent concerns are being focused on musk xylol, which was used to replace musk ambrette. Safety testing by the industry indicated that musk xylol was safe for use. Later studies outside the industry found musk xylol to be carcinogenic when fed to mice. Musk xylol has been used since the turn of the century. It accumulates in human tissue and has been found in human adipose tissue and breast milk.
Some fragrance materials are known to act as haptens in the skin. Although there is significant respiratory exposure to these materials, the possibility of respiratory sensitization has not been addressed. In some individuals with asthma, fragrances are primary triggers, whereas other irritants do not initiate a response. This suggests that there may be respiratory sensitization involved. If fragrance materials have the ability to sensitize the respiratory system in the same manner as the skin, the implications are serious and could be one factor in the unexplained increase in asthma rates.
The fragrance industry asserts that adequate safety testing is done, there is adequate monitoring of problems, and no increase in complaints concerning fragranced products has been noted. The present system of monitoring complaints is totally inadequate. The FDA's system of logging complaints is set up for users of the products, and not for those made ill by others' use. Someone who calls the general FDA complaint line may not be given instructions on whom to contact. Any complaints on "secondhand" fragrance should be addressed specifically to Lark Lambert, HFS-106, Office of Cosmetics and Colors, Cosmetic Adverse Reaction Monitoring Program, 200C Street S.W., Washington, DC 20204 USA. Telephone: (202) 205-4706. Fax: (202) 205-5098.
Even with the limited method of collecting data, there was an increase in records of complaints from 1995 to 1997. These complaints included respiratory and neurologic effects. The FDA suspended the Voluntary Cosmetic Registration Program in March 1998 because of budget cuts; it was reinstated 1 January 1999. This program is totally voluntary, and the industry is not required to participate.
The FDA only addresses the safety of materials in cosmetics. Fragrances in household products come under the jurisdiction of the Consumer Product Safety Commission. Once the products volatilize, air quality falls under U.S. Environmental Protection Agency jurisdiction. The fragrance industry does not have a centralized data collection program in place. This means that there is no method in place for accurately collecting data on the negative impact of fragrances.
The "trade-secret" status of fragrances makes it difficult, if not impossible, to pinpoint substances that cause problems. Present labeling is misleading, as "fragrance-free" and "unscented" products often contain fragrance chemicals. Avoidance is not possible when labeling does not reflect the contents.
It seems to be the industry's position to discount complaints concerning fragrances as reactionary and psychological responses to odors. Fragrances do enhance our lives, just as music does. But taste in music varies--what is music to one may be noise to another. Also, when there is too much noise or noise is too loud, real health problems occur.
When types of substances used by the fragrance industry are used in other industries, they are heavily regulated because of their known health effects. Whereas these substances are generally used at low levels in fragrance materials, the sheer numbers of fragranced products used and the constant exposure causes concern, especially in children. In addition, many of the materials have synergistic effects that cannot be ignored. A much more prudent course of action would be to gather reliable data, do further safety testing, pinpoint the substances causing problems, and eliminate them from use. Further information can be found at the web site of the Fragranced Products Information Network (http://www.ameliaww.com/fpin/fpin.htm).
Betty Bridges
Fragranced Products Information Network
Amelia, Virginia
E-mail: bcb56@ix.netcom.com
References and Notes
1. Spencer PS, Sterman AB, Horoupian DS, Foulds MM. Neurotoxic fragrance
produces ceroid and myelin disease. Science 204:633-635 (1979).
2. Troy WR. Toxicity of Versalide [letter]. Food Chem Toxicol 20:629 (1982).
3. Wisneski HS, Havery DC. Nitro musks in fragrance products: an update of FDA findings.
Cosmetics and Toiletries 3(6):73-74 (1996).
Lewis et al. (1) state that
compared to the fairly large number (> 400) of known rodent carcinogens, only a relatively small number of compounds (~ 20-30) have been shown to be carcinogenic in humans.
From this comparison, the authors seem to infer that animal bioassay cancer findings overpredict for human carcinogens. Of course, for most animal carcinogens there are no available epidemiologic data, and none planned, or for a few the findings are either inadequate or of limited value. In addition, few studies are under way or even planned on many known and potent animal carcinogens. Thus, one should realize that any conclusions about comparative numbers between animals and humans that are based on an apparent absence of data from humans can only be misleading and basically unusable for making any meaningful comparisons. A more relevant correlation to be made centers on the number of chemicals known to cause cancer in humans that have also been tested either prospectively or retrospectively in laboratory animals.
In any event, the numbers reported by these authors regarding known human carcinogens should be updated and modified using more current information. A proposed updated revision follows.
Utilizing data from the International Agency for Research on Cancer (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volumes 1-73) and the National Toxicology Program (NTP; Report on Carcinogens, editions 1-8), there are approximately 75 agents known to be causatively associated with cancer in humans and another 60 considered "probably carcinogenic to humans" (Table 1). With few exceptions, agents in both these categories have varying evidence of cancer in humans. While attempting to plan or implement cancer prevention strategies, the additional 225 agents considered by IARC as "possibly carcinogenic to humans" and the 169 agents judged by the NTP as "reasonably anticipated to be carcinogenic to humans" must be given close public health attention as well. Of course both lists must be compared to account for any duplications.
I have no particular disagreement with the number of 400 chemicals as being carcinogenic in animals, other than to emphasize that not all carcinogens are equal. That is, some chemicals cause multiple site cancer in both sexes of each strain and species, whereas others may induce tumors in a single organ in one sex of only one strain of rodent (2). Thus, one must evaluate the carcinogenicity data for each chemical rather than simplistically group chemicals that have been tested into two clusters by "positive" or "negative" results. In the NTP for example, of the 500 chemicals evaluated for carcinogenicity,
Consequently one should be more clear and more precise when using numbers of chemicals considered to be carcinogenic to rodents or/and to humans. To designate all chemicals that induce cancer in animals as being equal and representing similar and significant risks to humans is incorrect and improper, and should be avoided (4). Likewise, even though bioassays are indeed excellent surrogates for humans, not all chemicals shown to cause tumors in animals will, or should be expected to, prove to be carcinogenic to humans. Many reasons can be given for this lack of concordance, but a main one is that we should not expect the animal-to-human concordance to be perfect, largely for the reason mentioned: not all animal carcinogens are equal (that is, not equally potent or equally carcinogenic). Thus, chemicals such as d-limonene or allyl isothiocyanate that induce tumors only in the male rat kidney or urinary bladder are not in either the IARC or the NTP listings of carcinogens and clearly do not represent the likely cancer hazards that than do other more striking multiorgan, multistrain, and multispecies carcinogens do. Conversely, we know that all human carcinogens that have been tested adequately in animals are also carcinogenic to laboratory animals (5).
As shown in Table 1, the NTP has reviewed more than 800 chemicals as candidates for their Reports on Carcinogens, and only 198 agents have been judged as "known to be carcinogenic to humans" (29 agents) or as "reasonably anticipated to be carcinogenic to humans" (169 agents). IARC has reviewed and evaluated close to 850 agents in their Monographs program and found most of these (474 agents) inadequate for evaluation. Likewise for the NTP, many have been considered but few have been selected. Because many of the chemicals evaluated by IARC and the NTP are the same, although many are unique as well, one cannot simply add numerical data from these two sources without individual comparisons. Unfortunately, neither organization lists the agents that were considered but not selected for formal review because the available data are not considered adequate; that is, there may be no cancer data on a chemical, or the available data are insufficient to meet either agency's criteria for review.
Another issue posed by Lewis et al. (1) concerns the value of rodent bioassays. This has been an ongoing debate for many years. Some facts may be of interest. We know that all known human carcinogens that have been tested adequately in laboratory rodents are also carcinogenic to animals (2,4,6); for nearly 30 agents, the evidence of carcinogenicty was first observed in animals, ignored for the most part, and only subsequently detected in humans (7,8). These studies have all been accomplished using what some describe as the "maximum tolerated dose," which is at best operational terminology that has been literally misapplied and distorted, and is obsolete (9,10). A more accurate term is "minimally toxic dose" (MTD), or "minimally toxic exposure" (MTE), because when long-term bioassays are conducted, one must be certain that some adverse effects of the chemical are occurring, or the time, resources, and efforts will be wasted. Further, there is little evidence to support a "high-dose only" phenomenon in carcinogenesis. That is, using an MTD concept of exposure cannot "make" a chemical a carcinogen when it is a noncarcinogen (11).
I agree with Lewis et al. (1) that
in the safety evaluation of chemicals, we should be cautious in extrapolating results from experimental animal models to humans.
Conversely, I do not agree that we should ignore long-term bioassay results or delay preventative strategies until we have definitive mechanistic data, such as, for example, species differences and similarities in cytochrome P450 isoform carcinogen metabolic information, proposed by Lewis et al. (1). This does not mean such information will not be useful to the overall paradigm of quantifying carcinogenic risk in humans, but that equal cautions must be recognized in considering another in a lengthy line of mechanistic discoveries. This information may only modify or extend quantitative estimates of risk. On this issue, the distribution of these enzymes may be most useful for evaluating interindividual differences in susceptibility.
Thus, the public health value and usefulness of the bioassay for identifying potential or likely human carcinogens has a long history of being quite relevant and predictive. Perhaps we should give more attention to these laboratory results when attempting to prevent human cancers resulting from exposures to environmental or occupational carcinogens (12).
James Huff
NIEHS
Research Triangle Park, North Carolina
E-mail: huff1@niehs.nih.gov
References and Notes
1. Lewis DFV, Ioannides C, Parke DV. Cytochromes P450 and species
differences in xenobiotic metabolism and activation of carcinogen. Environ Health Perspect 106:633-641 (1998).
2. Huff JE. Value, validity, and historical development of carcinogenesis studies for
predicting and confirming carcinogenic risks to humans. In: Testing, Predicting, and Interpreting
Chemical Carcinogenicity (Kitchin KT, ed). New York:Marcel Dekker, 1999;21-123.
3. Fung VA, Barrett JC, Huff JE. The carcinogenesis bioassay in perspective: application in
identifying human cancer hazards. Environ Health Perspect 103:680-683 (1995).
4. Huff JE. Carcinogenesis results in animals predict cancer risks to humans. In:
Maxcy-Rosenau-Last Public Health & Preventive Medicine (Wallace RB, ed). 14th ed. Norwalk,
CT:Appleton-Lange, 1998;543-550, 567-569.
5. Huff JE. Chemicals causally associated with cancers in humans and in laboratory
animals: a perfect concordance. In: Carcinogenesis (Waalkes MP, Ward JM, eds). New York:Raven Press,1994;25-37.
6. Tomatis L, Aitio A, Wilbourn J, Shuker L. Human carcinogens identified so far.
Jpn J Cancer Res 80:795-807 (1989).
7. Tomatis L. The predictive value of rodent carcinogenicity tests in the evaluation
of human risks. Annu Rev Pharmacol Toxicol 19:511-530 (1979).
8. Huff J. Chemicals and cancer in humans: first evidence in experimental animals.
Environ Health Perspect 100:201-210 (1993).
9. Bucher JR, Portier CJ, Goodman JI, Faustman EM, Lucier GW. Workshop overview.
National Toxicology Program studies: principles of dose selection and applications to mechanistic
based risk assessment. Fundam Appl Toxicol 31:1-8 (1996).
10. Huff JE, Haseman JK, Rall DP. Scientific concepts, value, and significance of chemical
carcinogenesis studies. Annu Rev Pharmacol Toxicol 31:621-652 (1991).
11. Bucher JR. Doses in rodent cancer studies: sorting fact from fiction. Drug Metab Rev (in press).
12. Tomatis L, Huff JE, Hertz-Picciotto I, Sandler D, Bucher J, Boffetta P, Axelson O,
Blair A, Taylor J, Stayner L, et al. Avoided and avoidable risks in cancer. Carcinogenesis 18:97-105 (1997).
Last Updated: June 17, 1999