News and Reviews

Report on Alternatives Sessions at 10th International Congress of Toxicology (ICTX)

TAMPERE FINLAND 11-15 JULY 2004

A Symposium was held on 13 July at ICT-X, chaired by Dr Vera Rogiers (Vrije Universiteit Brussels] and Dr Hanna Tahti (Tampere University Finland).

Speakers included Dr Bernward Garthoff, from Bayer CropScience (Manheim GE); Phillip Botham, from CTL; Erik Walum, Biovitrum AB (Sweden), and Dr Angelo Vedani from Biographics Lab (Basel) was not able to get his elaborate Powerpoint presentation to function.

This symposium was clearly focused on the context of the REACH initiative in the EU Rogiers and Garthoff have served on expert committees to the EC on alternatives. Much was said of relevance to discussions and circumstances in the US.

Rogiers introduced the session by framing matters in the context of alternatives (3 Rs), meeting the demands of regulatory toxicity/safety assurances, and efficiency of resources. In the EU, she claimed that 61% of animal use is in pharma/medical safety studies, following by 30% used for tests to meet environmental regulations. Within this, 35% are used for acute toxicology studies and 17% for chronic tox testing. While she made reference to the challenges of validation, her main points were that for alternatives to have a “place at the table” methods must be available for all relevant endpoints, provide information that helps in prioritization, and that deliverables must be within realistic time frames. She noted that this last goal will require much more serious investments by governments and industry to increase the pace of R&D as well as validation.

Garthoff began his talk by noting the overarching role of trade agreements in determining the acceptability and actual use of alternatives. By this he meant that local laws, national programs, and even regional policy decisions must meet the test of WTO challenges if these occur. He made reference to HPV and CHEP in the US as well as devoting considerable time to explicating REACH. His main point was that the pace of disovering, developing, and validating alternatives is much too slow, noting that the first OECD resolution on alternatives was expressed in 1982. He characterized the EDC program by OECD, US and others as “a disaster in refinement” – presumably, he was referring to the largely abandoned original hopes that high throughput in vitro receptor based systems could replace whole animal testing.

He also commented on the role of alternatives in REACH, first noting that there is only one paragraph in REACH on alternatives. He also indicated that despite the frequently stated objective to develop and validate methods that provide the same information as stipulated in REACH and other EU regs, there is No inclusion of support for research on alternatives in the EU 6th Framework for research. He noted that the “pipeline” for new advances in alternatives, at the level of research, is running dry.

He referred to another EU program, SCALE [which I think means something like scientific project for awareness and evaluation of risks to children]: its emphases are on EDCs, neurodevelopment, and respiratory/immunotoxic risks. This initiative, which seems parallel at least in part to CHEP in the US, may engender another testing program and additional conflicts between the “precautionary principle” and animal welfare [in his terms].

He judged the cosmetics guidelines as “unrealistic” in the face of lack of support for research, basic and applied on developing alternatives. Similarly, he dismissed national and local laws on animal research and testing as inconsistent and not supportable by multinational corporations (like Bayer) that want consistency worldwide. His conclusions were: more coordination at the international level, increased resources to speed up the process from research to acceptance, especially challenging those in the public and political parties, who demand more information on more endpoints but do not support more research funding.

Botham entitled his talk “The scientific status of alternatives development.” He indicated, as did Rogiers that toxicology testing is not the main user of animals. Like Garthoff, he noted the demands for new endpoints conflicts with simultaneous demands for less animal toxicology testing; in addition, he indicated that some of the new endpoints [e.g., respiratory and neurodev] will present challenges to the development of valid alternatives. He also challenged those who see alternatives only for hazard identification, not risk assessment; if this is the view of alternatives, then they will never replace animal toxicology testing.

Interestingly, he echoed Garthoff’s concern over the state of support for developing alternatives, particularly at the basic research stage, to understand systems and mechanisms, which in his opinion are the basis of developing scientifically valid alternatives. He also noted that while the validation process is unduly long, that problem can be solved, whereas the problem of delays due to underfunding of relevant research is not being even considered. He expressed concern that there are fewer and fewer alternatives in the pipeline, stating that the “easy things” have been done, such as replacement methods for skin corrosion, phototox and dermal permeability – all of which, nonetheless, took years to accomplish. He held out more hope for refinement and reduction alternatives, such as changes in the acute toxicology methods, skin sensitivity, and local lymph node assay. He saw that refinement methods for acute oral toxicity, replacement methods for skin irritation and teratogenicity might be available by 5 years.

In his opinion, replacement methods for eye irritation, acute dermal/inhalation toxicity or respiratory sensitization may take 5-10 years, and he has the least expectation for alternative methods for acute ingestion toxicology, toxicokinetics, target organ/system toxicology, developmental/reproductive toxicology, or nongenotoxic carcinogenesis. This was a very thought provoking talk!

Walum focused on alternatives for prescreening sets of chemicals, and on endpoints related to cytotoxicity, barrier passage, and high throughput in vitro tests. He proposed that in vitro tests related to cytotoxicity and cellular kinetics can help define starting doses and possibly replace LD50 testing, but beyond that he did not appear to support continued work on cytotoxicity as an endpoint. He also pointed to the fact that while several cytotox tests have been accepted by the EU and OECD [although interlab validation is still in progress?], the US is not interested [true?]. On tests of barrier penetration, he indicated that the Caco-2 cell model is not working out. As an aside he noted the potential for using cells with transfected genes for transporters as tests of barrier passage. With respect of high throughput screening, he noted the use of these methods in pharmaceutical development, and suggested that these may be very useful for prioritization and sorting, but he also noted issues in interpretation and staging of subsequent testing.

Walum also raised the interesting concept of forward validation for some of the more novel endpoints in those cases where there really are no well validated “classical” toxicology tests, such as developmental immunotox. In such cases, he suggested that validating backwards to bad existing tests does not advance either science or regulatory decision making.

Rogiers presented the last talk, which was a description of a new initiative within the EU, called ECOPA [European Consensus Platform on 3R Alternatives]. This is a “quango” [quasi NGO] umbrella organization of national concensus platforms, including academic/govt/industry/NGO partners to facilitate exchange of information, expertise, and experience to enhance development of 3R alternatives through meetings, networks, publications. Also serves as a conduit for nominating persons for official committees. ECOPA is committed to involvement in public education through formulating and disseminating statements on key science/policy issues. Currently there are 11 full members [Austria, Belgium, Czech Republic, Finland, Germany, Italy, Netherlands, Spain, Sweden Switzerland, UK] with three associates (Denmark, Norway, Poland]. ECOPA has workgroups on research, education, politics, and ethics and is geared to respond to EU programs like REACH and SCALE to enhance the development of alternatives. Its achievements to date include: submission of formal comments on REACH and SCALE to the EC; establishing a website; supporting the organization of courses by national partners, and generally increasing research focus on alternatives. The 6th Framework providing some funding for ECOPA, and it is looking for some science initiatives to replenish the pipeline, as discussed earlier. Currently ECOPA has a stated interest in reprotox alternatives. [Seems like an interesting partner for CAAT!]

Ellen K. Silbergeld, Ph.D.
Johns Hopkins University
SOT, USA