Animal Welfare Information Center Newsletter, Spring 1996, Vol. 7 No. 1

Effects of the Shift to Alternatives on Industrial Practices

by
DeWayne H. Walker, D.V.M., M.S.
Manager, Laboratory Animal Research Services, 3M Corporation, St. Paul, Minnesota

Introduction
The Cosmetic Industry
Chemical and Household Products Industry
Pharmaceutical Industry
Medical Device Industry
Industrial Survey
The Worldwide Picture
Conclusions
References

Introduction

The intent of this article is to provide an overview of industrial proactivity in embracing the 3R's of alternatives--refinement, reduction, and replacement. Because of the diversity of industrial product lines, one can appreciate that one shoe does not fit all in terms of regulations, politics, marketing, and public opinion. It would be inappropriate to describe industry as a single entity in addressing alternative activity, but it does lend itself to analysis along the four classical industrial groups: cosmetics, household and industrial chemicals, pharmaceuticals, and medical devices.

In reality, public opinion has already broken industry up into categories if one acknowledges public sentiment regarding animal testing. Two 1990 polls, a Gallup Poll printed in Advertising Age and an unpublished Roper Poll conducted on behalf of industry, denoted similar data referencing society's impression of the use of animals in product testing (9, 6). These polls found that only one-third of those surveyed condoned the use of animals in the testing of cosmetics and household products. About one-half of those polled accepted animal usage in research for over-the-counter drugs, whereas the use of animals in testing of prescription drugs and medical devices was accepted by about two-thirds to three-quarters of those surveyed. One may venture the generalized statement that whereas drugs and medical devices appear to be viewed by the general public as necessities, cosmetics and household products appear to be viewed by the same public as niceties.

The Cosmetic Industry

The cosmetics industry is a $45-billion-a-year business with thousands of products embodied in 33 Food and Drug Administration (FDA) classifications (13,18). Cosmetics are defined by the Food, Drug and Cosmetic Act as "articles intended to be applied to the human body for cleaning, beautifying, promoting attractiveness or altering the appearance without affecting the body's structural function" (8). The key words in this definition are "intended" and "body's structural function." Intended use of the cosmetic must be clearly labeled and if the safety of a cosmetic product is not adequately substantiated for that intended use, the product is considered misbranded and may be subject to regulatory action. The physiological, or functional, altering of the body differentiates drugs from cosmetics. The FDA regulates this difference by not requiring premarket approval of cosmetics. At the same time, however, the FDA does expect that the manufacturer of a cosmetic has conducted toxicological and other appropriate tests to substantiate the safety of the product and can provide this data if challenged by the agency. While it has become fashionable for some manufacturers to apply the "cruelty-free" label to their products (indicating that animals were not used during safety testing), this claim can be misleading (see sidebar--The Cruelty-Free Label).

In vitro tests and other nonanimal methods for safety evaluation have come a long way and are being used in industry as initial screening procedures. However, given a new cosmetic derivative or a cosmetic incorporating a drug component, a standardized in vivo test, such as the Draize Ocular Irritation Test, may be in order. This in vivo test is still considered valuable in predicting human eye irritants when the irritation is subtle or when the chronic recovery phase data may be equally as important as the initial acute exposure data. Industry, in cooperation with regulatory agencies, has established multiple refinements to obtain the required data while minimizing the potential for pain or distress. Evaluation of the agent's pH and the use of the primary dermal irritation tests are routinely used to screen out agents likely to evoke a response beyond moderate irritation (17). Agents having passed the preliminary screening could conceivably go on to the classic test but with the following refinements in place: use of three animals vs. the standard of six; use of smaller volumes of solution installed in the eye; use of one animal to evaluate an unknown and await a response before continuing or discontinuing with the remaining test animals; and use, when applicable, of anesthetics in the eye (10). In part, because of refinements to the Draize Ocular Irritation Test and use of available in vitro methods, the number of rabbits used in the cosmetic industry between 1980 and 1989 was reduced by 87 percent (12).

Chemical and Household Products Industry

The household and industrial chemical group is extremely diverse, touching all our lives every day in the home, the workplace, and the outdoors. The Environmental Protection Agency (EPA) has listed over 100,000 chemicals in our environment, with several thousand new chemicals being added each year (11). The definition of this group is "those products that are of a non-medical nature that are created to enhance personal, household, industrial and agricultural applications." This group is also under attack by animal activists and, in fact, People for the Ethical Treatment of Animals (PETA) has a Top 50 product boycott list that includes many companies supplying these products (4). However, the chemical and household products group, unlike the cosmetic group, is frequently called on by government agencies to provide safety data obtained from in vivo testing. A risk assessment of a given chemical may be required by: the U.S. Department of Transportation (DOT) to classify chemicals for handling and transportation; the Occupational Safety and Health Administration seeking to protect workers via the manufacturer identifying "gross, mostly local toxic effects"; and the Environmental Protection Agency to assess the potential environmental impact of a products release into the environment. Needless to say, the general population expects the manufacturer to provide toxicological data should there be accidental or deliberate exposure. The poison control centers in the United States receive on average 1.6 million calls a year; 900,000 of these calls relate to accidental poisoning of children and about 40,000 to animal poisoning. (14) The bottom line is an obvious need to safeguard the general public from accidental injury and to achieve this data through effective product testing.

In the area of alternatives for this industrial group, we find the introduction of the Corrositex Test. This test, introduced in 1993, marked the first acceptance by a Federal agency (DOT) of an in vitro test as an alternative to animal testing for regulatory purposes (21). The corrosive classification of a given chemical can be determined by this test based on the time it takes the chemical to cause damage to a collagen matrix top layer, which approximates a full-thickness layer of skin cells, and elicit a color indicator response in a second layer. Although there are categories of chemicals for which this test is not applicable, the test has been shown to be 97.7 percent accurate in identifying all commercially available corrosive chemicals on the Department of Transportation Hazardous Material Table (5).

Pharmaceutical Industry

A drug is defined as "an article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans and other animals; and articles (other than food) intended to affect the structure or any function of the body of humans or other animals." (8) The pharmaceutical industry is an area of great potential for development of alternatives to animal testing. Whereas cosmetic/consumer products impart there benefit with little or no effect on physiological functions, drugs purposely affect the biological processes controlling life. As a consequence, drug interaction necessitates considerable investigation to ensure both efficacy and safety. Drug introduction to market is an extremely expensive and time-consuming endeavor. While a cosmetic may take but 6 months to reach the consumer, and a typical consumer/industrial chemical 2 to 3 years and $1 to $2 million to get to market, that is but a blink of an eye and pocket change to the drug industry (18). In the process of drug development and approval, an average of 6.5 years is spent in the screening and preclinical testing of as many as 5,000 candidate compounds. Only 5 of 5,000 compounds that enter preclinical testing make it to human testing, which consumes another 6 years. FDA review and approval entails on average another 2.5 years, and typically only 1 of the 5 drugs will be approved. The bottom line is an average of 15 years from laboratory to medicine chest at an investment cost of $359 million. The Pharmaceutical Research and Manufacturers of America estimates that this will reach $1 billion in cost per drug early in the next century (2).

Although the cost and time associated with clinical testing and FDA review may be inescapable now and in the future, the use of in vitro methods in the discovery and preclinical phase has been instrumental in streamlining these stages. Computer modeling and structure-activity relationships have been invaluable in the early screening of candidate drugs. Agar overlay for cytotoxicity, Ames mutagenicity assay, cell transformation assay, and yeast mutagenicity assay are among those tests in common use for early toxicity screening. In the preclinical phase, a meaningful reduction in animal numbers has been attributed to the use of tiered testing, approximate lethal dose, and the Up and Down Method to replace the classic LD50 (3).

Medical Device Industry

Finally, there is the medical device industry. Medical devices are defined as, "any health care product that does not achieve any of its principal intended purposes by chemical action in or on the body or by being metabolized" (8). This group consistently fares well in animal use surveys, likely because of the perception by the general public that the products they generate have immediate and measurable impact on the quality of life and the saving of lives.

To accomplish their intended purpose, medical devices require varying degrees of invasiveness, which in turn necessitates various levels of safety and efficacy testing. Medical devices are evaluated by a scheme consisting of a battery of in vitro and in vivo tests (19). For those devices that are in contact with the intact skin only, the normal scheme requires the:

intracutaneous irritation test in the rabbit
maximization test for hypersensitivity in the guinea pig
cytotoxicity via agar overlay
acute systemic test in mice
For those medical devices passed into the body, such as catheters, the testing includes tests 1-4 above plus:
in vitro hemolysis in whole blood
rabbit pyrogen or in vitro Limulus amebocyte lysate (LAL) for pyrogenic effect
rabbit muscle implants for biocompatibility
Ames mutagenicity to evaluate mutagenic potential
For those devices implanted for a period in excess of 30 days, such as heart valves, tests 1-8 are required as well as:
chronic toxicity
carcinogenesis testing

In reviewing the tests making up the evaluation scheme, a major area for development of alternatives is that of biocompatibility testing. The interaction of implanted biomaterials on the body tissues is an area that has received much attention as a result of the controversy surrounding breast implants. The present in vivo methods involve a considerable investment of time and resources with enough scientific uncertainty in the results to suggest the need for the investigation of in vitro methods to either replace or supplement these tests. In the meantime, the medical device industry has done a good job of embracing alternative methods for training. Such implements as surgery computer simulation, foam cadavers, mannequins, use of cadaver tissues for laser training, and the laparoscopic "black box" have been useful adjuncts in common use in this industrial group. In the research and development phase, such refinements as telemetry implants, vascular access ports, and electronic access ports have been well-received alternatives to more invasive data collection methods.

Industrial Survey

To augment this general overview of how alternatives affect industrial practices, a small (n=14) informal survey was conducted among companies representing the cosmetic/chemical and drug/medical device industries. The intent of the survey was to ascertain the general attitude of the industries towards the consideration, or experience in use, of alternative methods. In general, all industries indicated an appreciation for the coming of age of alternative methods; however, as one might predict, there was a difference of opinion between the two groups. Questions were presented with a range response of "strongly agree" to "strongly disagree" with additional comments encouraged. Those questions invoking the most interesting responses are noted below:

"Your firm's move to consideration of alternatives is/was influenced by the animal activism movement"? The response was not too unexpected as cosmetic/chemical companies indicated an agreement to strong agreement with this statement. Drug and medical device companies were neutral to indicating disagreement with the statement. This result aligned well with the public opinion of increased acceptance of animal usage for the drug and medical device industry.
"Your firm's move to consideration of alternatives is/was influenced by direct monetary considerations"? The response for the cosmetic/chemical group was somewhat surprising. One would expect that some test cost savings would be achieved by these groups given their significant experience with non-animal alternatives. However, the majority responded as disagreeing with the statement. The plausible explanation is that even if cost savings are presently being realized, the use of alternative tests has yet to recover the costs of development and validation of these methods. Drug and medical device companies were neutral on this question, likely indicating inadequate experience to pass judgment.
"Your firm's move to consideration of alternatives is/was influenced by indirect monetary considerations"? Both cosmetic/chemical and drug/medical device companies were neutral when answering this question on using alternatives as a marketing tool. Given the use of "cruelty-free" advertising by some beauty product firms, this result may seem inconsistent on the part of the cosmetic firms. However, the cosmetic companies surveyed were major reputable companies claiming a strong aversion to seeking a market advantage through such advertising.

Each group was surveyed as to their main change in business practices since the advent of alternatives. The cosmetic/chemical group emphasized public opinion aspects, notably: animal work is reviewed at a much higher administration level, increased use of human subjects, and establishment of much stronger public relations departments. The drug and medical device group laid most emphasis on scientific enhancements noting increased management involvement in test selection, an enhanced level of innovative thinking about the feasibility of alternatives, and a noticeable improvement in acceptance and use of validated nonanimal methods.

When questioned on what nonanimal tests were being used by their firms, the groups reported that: all are currently using structure-activity relationships, deductions based on similar products, cell cultures, and comprehensive literature searches for toxicity of raw materials. The cosmetic and chemical industries use commercially available artificial tissues and drugs/medical device industries use well-established in vitro methods such as agar overlay for cytotoxicity, Ames mutagenicity assay, and cell transformation assay. Given the opportunity to add to this survey list, the cosmetic/chemical group noted that they are using the bovine corneal opacity test, chorioallantoic membrane test, and yeast phototoxicity assay. Drug and medical device groups are using combinatorial chemistry, gene sequencing, and tissue slices.

The Worldwide Picture

The industrial market is a worldwide market, so legislation affecting one region can have significant repercussions on the far side of the globe. Such may be the case with impending enforcement of legislation in Europe. In 1986, Directive 86/609/EEC was passed into law establishing a European commitment to the 3R's--reduction in number of animals used, refined techniques to minimize pain, and replacement of live animals with nonanimal techniques. In particular, article 7.2 states, "An experiment shall not be performed, if another scientifically satisfactory method of obtaining the result sought, not entailing the use of an animal, is reasonable and practicably available." In 1991 the Commission of the European Communities consummated the push for alternative procedures by the establishment of the European Centre for the Validation of Alternative Methods (ECVAM) (20). This melting pot of European scientists was tasked with coordinating the validation of alternative test methods, functioning as a focal point for information exchange, establishing and managing an alternative data base, and promoting an international dialogue for encouraging the development, validation, and regulatory acceptance of alternative test methods (1). This sequence of events took on potential worldwide market impact when on June 14, 1993, the Council of Ministers approved a 6th Amendment to the Cosmetic Directive 76/768/EEC. The preamble of this document includes the following background statement with reference to cosmetics:
"whereas testing on animals of ingredients or combinations of ingredients should be banned as from 1 January, 1998."

The directive came with the loophole that should the ECVAM scientists not demonstrate scientifically equivalent nonanimal test methods, the deadline could be extended minimally another 2 years (15). However, ECVAM progress to date would indicate the probability of some methods meeting this criteria by the January 1, 1998 date (16).

The potential impact of the EEC Directives is of future concern mostly from the perspective of interpretation. The question may be asked, "Will U.S. regulators accept European alternative methods and validation procedures? Will there be an agreement on the vagueness of ingredients vs. final formulation?; that is, if a U.S. company initially develops a product with intent for it to be a drug, thereby likely requiring some animal testing, what if later it is not efficacious as a drug but would suit as a cosmetic. Does the initial animal testing of the chemical disqualify it for later reclassification? Will the varying U.S. and European definition of cosmetics result in major consequences for multi-nationals (that is, trade barriers)? For example, in the United States, such products as sunscreens, antiperspirants, antibacterial soaps, and fluoride tooth paste are considered drugs, whereas in Europe they are considered cosmetics. A company is, thus, in the potential bind of satisfying U.S. regulators by performing safety animal testing only to be disqualified in the European market with the same product because it has undergone animal testing.

Conclusions

It is perhaps fair to say that at this point in time the cosmetic and, to a lesser degree, the chemical industries have embraced alternative methods that primarily support the R's of reduction and replacement. The drug and medical device industries have likewise demonstrated success in the R of reduction and meaningful advancements in refinements. The R of replacement is likely a long-term consideration for the drug and device industries given the complexity of their respective chemical/material entities and their purposeful direct interaction with the body. It is generally encouraging to see the extent of alternative usage or at least consideration of alternatives across all of the industrial groups surveyed. It is apparent that, for the future, the financial impact of market barriers resulting from laws requiring alternatives may be a far greater direct influence on development and use of alternatives than public opinion and the animal activism movement. As in vitro tests are developed and validated, and harmony is established between regulatory bodies and international groups, the full spectrum of the 3R's will be hopefully realized.

For more information, Dr. Walker may be contacted at phone: (612) 736-3747, fax: (612) 736-1519, e-mail: dhwalker@mmm.com or by writing to 3M Corporation, Bldg. 270-2A-08, 3M Center, St. Paul, MN 55144-1000.

References

Balls, M. and E. Marafante, (1993). The way forward: the part to be played by ECVAM. Joint EFPIA/EC Workshop on Harmonisation of Training in Laboratory Animal Science.
Beary, J.F. (1995). The drug development and approval process. New Drug Approvals in 1995, Pharmaceutical Research and Manufacturers of America: Washington, DC.
Breen, B. (1993). Why we need animal testing. Garbage April/May: 38-45.
Caring Consumer Cruelty-Free Shopping Guide. (1995). People for the Ethical Treatment of Animals Fall/Winter.
Corrositex@ Instruction Manual. (1994). p.6.
The Council for Health and Safety Research Education(1990). Public attitudes toward the use of animals for medical research and health and safety testing. A study by The Roper Organization.
Entine, J. (1994). Shattered image. Business Ethics Sept/Oct: 23-28.
Food and Drug Administration (1989). Requirements of Laws and Regulations Enforced by the U.S. Food and Drug Administration, DHHS Publication No. (FDA) 89-1115, U.S. Department of Health and Human Services, Public Health Service, Washington, D.C.
Freeman, L. and A. Ward (1990). Animal uproar; when testing for human health and safety is the issue, beauty-aids marketers struggle to define 'humane.' Advertising Age 61(9):S1-2.
Gad, S.C. (1995). Overview of in vitro ocular irritation test systems and an evaluation of their status. In Animal Test Alternatives , Harry Salem, ed., Mercel Dekker: New York.
Goldberg, A.M. (1989). Alternatives in toxicology. Cosmetics and Toiletries 104:53-56.
The Humane Society of the United States (1993). Fact Sheet: The Draize Eye-Irritancy Test.
Jackson, E.M. (1991). Cosmetics: substantiating safety. In Dermatotoxicity, 4th ed., F.N. Marzulli and H.I. Mailbach, eds., Hemisphere Publishing Corp.: New York.
Join Hands (1995). Consumer Product Safety: Why we need it, how we achieve it. A booklet by Join Hands.
Official Journal of the European Communities (1993). Council Directive 93/36/EEC, amending, for the sixth time, Directive 76/768/EEC on the approximation of the Member States relating to cosmetic products. L151, p32.
Personal conversation with Dr. Michael Balls, Director of ECVAM, November 1995.
Seabaugh, V.M. (1995). Ocular testing: historical perspectives. Animal Test Alternatives, Harry Salem, ed., Mercel Dekker: New York.
Stephens, T.J. and E.T. Spence (1995). The role of in vitro tests in assessing the safety of cosmetics and consumer products. In Animal Test Alternatives, 1st ed., Harry Salem, ed., Mercel Dekker: New York.
Toxicology Sub-Group of the Tripartite Sub-Committee on Medical Devices (1986). Tripartite Biocompatibility Guidance for Medical Devices.
Trends and Alternatives in Testing, The Joseph F. Morgan Research Foundation Newsletter (1995). The governmental face of alternatives. Winter/Spring: 2-3.
Trends and Alternatives in Testing, The Joseph F. Morgan Research Foundation Newsletter (1994). A first!. Spring/Summer: 4-5.

This article appeared in the Animal Welfare Information Center Newsletter, Volume 7, Number 1, Spring 1996

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