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PubMedDate not supplied

Lessons learned from validation of in vitro toxicity test: from failure to acceptance into regulatory practice.

As no scientific approach or regulatory guidelines existed for the experimental validation of in vitro toxicity tests, in 1990 a US/European validation workshop agreed in Amden (Switzerland) on a simple definition of the validation process. Several international validation studies failed, although they were conducted according to these recommendations. Taking into account the lessons learned from this experience, a second validation workshop was held by ECVAM in Amden in 1994 to develop a more precisely defined validation concept. Prevalidation and the development of biostatistically defined prediction models were added as essential elements to the validation process. In 1995/1996 the ECVAM validation procedure was officially accepted by EU member countries and at the international level by the US regulatory agencies and the OECD. The improved validation concept was immediately introduced into ongoing validation studies. In 1996 the ECVAM/COLIPA validation study of the in vitro phototoxicity test, which was conducted according to the ECVAM/OECD validation concept, was finished successfully and in 1998 a supporting study on UV-filter chemicals was undertaken. In 1998 the 3T3 NRU PT in vitro phototoxicity test was the first experimentally validated in vitro toxicity test that was recommended for regulatory purposes by ESAC, the ECVAM Scientific Advisory Committee, and by the DG ENV of the EU Commission. Meanwhile, two in vitro skin corrosivity tests have successfully been validated by ECVAM. Finally, in June 2000 the three experimentally validated tests were accepted by EU member states for regulatory purposes as the first in vitro toxicity tests. In addition, ECVAM has funded a successful validation study of three in vitro embryotoxicity tests, which was conducted in 12 European laboratories and finished in July 2000. The three tests validated in this study were the whole embryo culture (WEC) test applied to rat embryos, the micromass (MM) test employing primary cultures of dissociated mouse limb bud cells and the mouse embryonic stem cell test (EST). Examples will be given of successful validation studies during the past decade with particular reference to in vitro toxicity tests that were evaluated for regulatory purposes either by the US validation centre ICCVAM or ECVAM in the fields of sensitisation, phototoxicity and embryotoxicity

Animal Testing Alternatives↗
PubMed2002

Relative sensitivity of one freshwater and two marine acute toxicity tests as determined by testing 30 offshore E & P chemicals.

Acute toxicity of 30 offshore E & P (Exploration and Production) chemicals was measured using the three standard test organisms Daphnia magna (freshwater cladoceran), Acartia tonsa (marine copepod) and Skeletonema costatum (marine diatom alga). Test chemicals included 20 water-soluble and 10 (partially) non-soluble products. For 22 out of the 30 chemicals, the difference in sensitivity between the three tests varied within one order of magnitude. A very good correlation was found between the two marine tests (r = 0.96, P < 0.01, n = 30), and a correlation coefficient of r = 0.78 (P < 0.01, n = 30) was found between D. magna and both A. tonsa and S. costatum, individually. When the comparison of D. magna and A. tonsa sensitivity was based only on the water-soluble chemicals, a significantly higher correlation was obtained (r = 0.84, n = 20), indicating that the sample preparation method used for the (partially) non-soluble chemicals (the water accommodated fraction (WAF) method) induces additional variation between tests performed with different test media. (Partially) non-soluble chemicals are characterised by phase separation or precipitation at the concentrations used for testing. In a WAF-based test, each test concentration/exposure level is prepared separately, and following mixing and separation, only the water phase is used for testing. Toxicity is related to the amount of substance originally added to the mixing vessels. For 25 of the 30 chemicals, D. magna was found to be less sensitive than the marine copepod by a factor >2. The generally higher sensitivity of the marine toxicity tests compared to the Daphnia test emphasise the importance of using marine data for environmental hazard classification as well as for environmental risk assessment purposes.

Animals↗
PubMed2005

Microbial characterization of artificial sediment and comparisons with natural sediments--implications for toxicity testing.

The development and activity of microbiota in artificial sediment may have strong implications for the fate of test compounds and the outcome of toxicity tests. In this study, we compare a number of microbial variables in the artificial sediment commonly used in toxicity testing with that of natural sediments. Bacterial abundance of artificial sediment ranged 5.7 to 7.1 x 10(8) cells/g wet weight, which is about two orders of magnitude lower than values commonly reported for natural sediments. Similarly, alternative estimates of microbial biomass (sum of phospholipid fatty acid, ergosterol, adenosine triphosphate) were several times lower for artificial sediment compared with natural sediment. Bacterial activity (3H-thymidine incorporation) ranged 4.0 to 7.4 pmol g(-1) h(-1) (or 0.062-0.113 microg C g(-1) h(-1)) in artificial sediments, which is low compared with values commonly reported for freshwater sediments. Community respiration in artificial sediment was 34 to 93 microg CO2 g(-1) d(-1). Bacterial community composition assessed by terminal restriction fragment length polymorphism of polymerase chain reaction amplified 16S rRNA genes demonstrated that natural bacterial communities appear to be more diverse than their counterparts in artificial sediment. The average similarity of the microbial communities obtained by this method was less than 40%, and different operational taxonomic units appeared to dominate the artificial and natural sediment, respectively. These results and supporting data from previous studies in natural sediments suggest that the artificial sediment has a poorly developed microbial component that differs substantially from that in natural sediments.

Biomass↗
PubMed1975

Acute and prolonged toxicity tests.

An answer to the question of whether acute and prolonged toxicity tests are good candidates for standardization is developed by reviewing (1) the factors that are presumed to influence the results of these tests and (2) the collaborative studies that have been reported in the literature. In regard to acute toxicity tests it is clear that competent laboratories give due consideration for the control of factors that are known to influence these tests. Also competent laboratories using their own procedures provide reliable results, even though the procedures vary from laboratory to laboratory. In regard to prolonged toxicity tests there are no examples of controlled collaborative investigations which could be used to evaluate interlaboratory variation and its relation to the protocols involved. It is recommended that guidelines rather than rigid protocols would be an appropriate approach for improving the quality and accuracy of these toxicologic tests. Examples of such guidelines are given.

Biological Assay↗
PubMed1992

Alternative acute inhalation toxicity testing by determination of the concentration-time-mortality relationship: experimental comparison with standard LC50 testing.

A new design for acute inhalation toxicity testing was evaluated and compared with results obtained according to OECD guideline 403. The new design consists of a range-finding test, which is compatible with a conventional limit test, and can be followed by determination of a concentration-time-mortality relationship, enabling calculation of LC50 (50% mortality exposure concentration) values. By exposing pairs of rats for different periods of time to about four different test concentrations in a nose-only exposure unit, LT50 (50% mortality exposure time) values were obtained for five pairs of animals per concentration. The mortality data of the approximate 20 time-concentration combinations were used to calculate the probit relationship. Estimated mortality responses from these probit relations were compared with mortality figures obtained by exposing groups of five male rats and five female rats whole-body according to conventional toxicity testing. In general, there was good correspondence between the estimated and the observed mortality response. In our hands, the determination of the concentration-time-mortality relationship takes about the same number of animals (40-50) as the conventional LC50 procedure according to the OECD guideline 403. However, the new method has several additional advantages such as: (A) LC50 values are obtained over a 10-fold range in time, with the potential of decreasing the number of animals used when regulations require acute toxicity data for different periods of exposure. (B) The obtained relationship contains considerably more valuable information for risk assessment than the LC50 value.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1983

Differentiated cell and organ culture in toxicity testing.

The safety evaluation of new chemicals involves a range of investigations, including acute and sub-acute toxicity testing, long-term toxicity testing, studies on mutagenicity, carcinogenicity, and reproductive toxicity, and special investigations involving the interaction of the chemical under test with particular parts of the body, such as the skin or the nervous system. We shall consider the potential role of differentiated cell and organ culture in toxicity testing, and the criteria available for assessing cell viability, damage, and death, with a view to establishing whether such methods could be used for determining the relative acute toxicities of chemicals. We shall also consider methods for studying the effects of chemicals on general and specific aspects of cell structure and function, including liver cell and organ cultures both as primary targets themselves susceptible to damage and as providers of metabolically activated compounds able to affect other cells and tissues.

Animals↗
PubMed1986

Oil gavage test-compound administration effects in NTP carcinogenesis-toxicity testing.

Consulting toxicologists began in 1982 to question the use and potential involvement of oil gavage test-compound administration in unexpected NTP carcinogenesis responses. Investigations have focused on corn oil gavage alternatives, vehicle type and volume, alteration of MTD, teratogenic effects, disposition of test compounds, and target tissues. Micoencapsulation will require considerable development research to make it a suitable alternative. Vehicle type and volume appear to have different effects on the apparent MTD, teratogenicity and disposition of very similar compounds. Only two tissue effects have been observed in the NTP oil gavage bioassay data. First, there is a sporadic and weak association with exocrine pancreatic acinar cell proliferative lesions; these lesions are highly correlated with overweight male Fischer 344/N rats. Second, leukemia is reduced about 50 percent in the male Fischer 344/N rats; this is a strong association which results in an 8-10 percent increase in survival. The protective effect of corn oil gavage is remarkable and there is no significant enhancement of tumor development. Corn oil gavage under the conditions of the NTP carcinogenesis bioassay does contribute to overnutrition and undesirable increased body weight, especially in male Fischer 344/N rats. The NTP and NCTR research programs include research plans to address critical oil gavage, diet composition feeding regimen, exercise and hormonal status questions. Results of these studies will point the way to improving long-term carcinogenesis and toxicity testing.

Animals↗
PubMed2001

A 48-h larval development toxicity test using the marine polychaete Galeolaria caespitosa Lamarck (Fam. Serpulidae).

Assessing the risk of effluents and other anthropogenic inputs to the receiving environment is ultimately best done on a site-specific basis, which often requires toxicity tests using organisms relevant to that environment. Additionally, the test species or life stage needs to be available for a reasonable portion of the year to allow temporal fluctuations to be assessed. A 48-h larval development toxicity test using the marine polychaete Galeolaria caespitosa was developed. This test was developed as G. caespitosa releases viable gametes year-round, and the test species is environmentally relevant to the marine system receiving the liquid effluent being evaluated. Toxicity tests were conducted using G. caespitosa from different locations and evaluating the gamete response to copper. All population responses were comparable, with EC50 values ranging from 16 to 40 microg/L copper (as CuCl2, x 2H2O). Toxicity tests were also conducted using G. caespitosa gametes with an effluent produced by a lead smelting operation. The response of the G. caespitosa test with this effluent was compared with three other test methods using two microalgal species, Isochrysis sp. and Nitzschia closterium, and gametes from the mussel Mytilus edulis. The G. caespitosa larval development toxicity test was the most sensitive test to the effluent, with EC50 values ranging from 1-23% effluent, while it ranked second in sensitivity to copper. This test could be applied to other common serpulids worldwide.

Animals↗
PubMed2001

Sublethal effects of silver in zooplankton: importance of exposure pathways and implications for toxicity testing.

In aquatic environments, organisms are exposed to contaminants via direct uptake from water and by trophic transfer. However, most toxicity tests only examine uptake via the dissolved phase. We compared the response of marine and freshwater crustacean zooplankton to silver following dissolved and food exposure. Silver, like other metals, concentrates in aquatic food chains and may exert toxicity. In standard solute exposure toxicity tests, Ag is toxic to zooplankton at concentrations of 400 nM for marine copepods and 100 nM for freshwater cladocerans, concentrations far greater than those in most waters. However, if Ag is accumulated from algal food, reproductive success decreases by >50% when algae are exposed to only 1 nM Ag in copepods and 0.5 nM Ag in cladocerans. These concentrations are within an order of magnitude of those found in contaminated estuaries. Following dietary exposure, decreased egg production and viability occur when tissue Ag concentrations increase three- to fourfold to 0.3 ppm in cladocerans and 0.5 ppm in copepods. Assimilated Ag depresses egg production by reducing yolk protein deposition and ovarian development. Our results indicate that ecologically relevant toxicity tests should consider sublethal effects of contaminants obtained from food since these effects cannot be predicted from exposures to only dissolved contaminants.

Animals↗
PubMed1985

Rat peritoneal implantation test. A new method for tissue toxicity testing of urinary catheters.

Severe urethral inflammatory reactions followed by strictures have been reported after short-term catheterisation with latex catheters since 1982. In this study a new method for assessing tissue toxicity is presented. It is based on the degree of inhibition of rat peritoneal foreign body reaction. Because the results are easier to interpret and more quantitative than those of the rabbit muscle implantation test, the rat peritoneal implantation test is recommended as a standard in vivo toxicity test.

Animals↗
PubMed2004

History and rationale of genetic toxicity testing: an impersonal, and sometimes personal, view.

Genetic toxicity testing is a necessary and pivotal component of product development and registration. This article traces the historical development and evolution of genetic toxicity testing, and the rationale for such testing, and identifies some of the individuals who played key roles in this process. The evolution of the present test batteries and some of the research and rationales behind the decisions to accept or reject tests are described.

Animals↗
PubMed2002

A ten year summary of concurrent ambient water column and sediment toxicity tests in the Chesapeake Bay watershed: 1990-1999.

The goal of this study was to identify the relative toxicity of ambient areas in the Chesapeake Bay watershed by using a suite of concurrent water column and sediment toxicity tests at seventy-five ambient stations in 20 Chesapeake Bay rivers from 1990 through 1999. Spatial and temporal variability was examined at selected locations throughout the 10 yr study. Inorganic and organic contaminants were evaluated in ambient water and sediment concurrently with water column and sediment tests to assess possible causes of toxicity although absolute causality can not be established. Multivariate statistical analysis was used to develop a multiple endpoint toxicity index (TOX-INDEX) at each station for both water column and sediment toxicity data. Water column tests from the 10 yr testing period showed that 49% of the time, some degree of toxicity was reported. The most toxic sites based on water column results were located in urbanized areas such as the Anacostia River, Elizabeth River and the Middle River. Water quality criteria for copper, lead, mercury, nickel and zinc were exceeded at one or more of these sites. Water column toxicity was also reported in localized areas of the South and Chester Rivers. Both spatial and temporal variability was reported from the suite of water column toxicity tests. Some degree of sediment toxicity was reported from 62% of the tests conducted during the ten year period. The Elizabeth River and Baltimore Harbor stations were reported as the most toxic areas based on sediment results. Sediment toxicity guidelines were exceeded for one or more of the following metals at these two locations: arsenic, cadmium, chromium, copper, lead, nickel and zinc. At the Elizabeth River stations nine of sixteen semi-volatile organics and two of seven pesticides measured exceeded the ER-M values in 1990. Ambient sediment toxicity tests in the Elizabeth River in 1996 showed reduced toxicity. Various semi-volatile organics exceeded the ER-M values at a number of Baltimore Harbor sites; pyrene and dibenzo(a,h)anthracene were particularly high at one of the stations (Northwest Harbor). Localized sediment toxicity was also reported in the Chester, James, Magothy, Rappahannock, and Potomac Rivers but the link with contaminants was not determined. Both spatial and temporal variability was less for sediment toxicity data when compared with water column toxicity data. A comparison of water column and sediment toxicity data for the various stations over the 10 yr study showed that approximately half the time agreement occurred (either both suite of tests showed toxicity or neither suite of tests showed toxicity).

Animals↗
PubMed1992

[A study of the relationships between exposure periods and no-effect doses in repeated dose toxicity tests].

In the risk assessment of chemicals to humans, it is a very important step to determine no-observed-adverse-effect-levels (NOAEL) or lowest-observed-adverse-effect-levels (LOAEL) from animal experiments. Recently, short-term screening tests, such as 28-day repeated dose toxicity test, are carried out in accordance with the regulative guidelines for the safety evaluation of chemicals. However, many problems still remain in the risk assessment to human based on short-term toxicity studies. For this reason, we studied the relationships between the exposure periods and NOAELs or LOAELs in repeated dose toxicity tests using available test results of 18 halogenated compounds. The ratios between each NOAEL or LOAEL of short-term tests (14, 28 days, 13 weeks and 6 month) and those of long-term tests (longer than one year) were calculated on the basis of same animal species, route and toxic effect. From this study, it was considered that exposures above 13 weeks were needed to satisfy the present safety factor considerations for setting an acceptable daily intake (ADI).

Administration, Inhalation↗
PubMed1995

Immobilised yeast cells biosensor for total toxicity testing.

An immobilised yeast cell biosensor has been developed for the total toxicity testing of a sample that may contain a number of different pollutant species; the biosensor uses an amperometric gas diffusion oxygen as indicator electrode. The method is based on the perturbation of the respiratory activity of a yeast, Saccharomyces cerevisiae, immobilised on an agar gel containing the culture medium (i.e., 'agarised medium'), by the toxic test substance. Glucose is used as substrate while the toxic substances tested consist of several metallic ions, phenol and cationic or anionic surfactants.

Biosensing Techniques↗
PubMed2002

Evaluation of reduced sediment volume toxicity test procedures using the marine amphipod Ampelisca abdita.

During the past 20 years, the role of sediment toxicity tests has expanded from testing of primarily dredged material to risk assessment, decontamination technologies, large-scale regional sediment-quality assessments, and toxicity identification evaluations. Sediment toxicity tests are needed that can provide reliable data using less sediment and smaller test chambers, thus utilizing resources more efficiently. We compared survival results from 10-d standard marine amphipod tests at 20 degrees C using 200 ml of sediment to reduced-volume tests containing 20 or 50 ml of sediment and found no significant differences. Similar survival also was observed in tests conducted for 7-d at 23 degrees C versus the standard 10-d exposure at 20 degrees C. However, amphipod sensitivity was significantly less in reduced-volume tests conducted for only 4- or 7-d at 20 degrees C. The 10-d sediment toxicity tests using 50 ml of sediment provided comparable results to the standard protocol, whereas time for sampling, preparing, and sieving sediments for a test was substantially reduced.

Amphipoda↗
PubMed2001

Lactate dehydrogenase activity as an effect criterion in toxicity tests with Daphnia magna straus.

Activity of lactate dehydrogenase (LDH) was used as an effect criterion in toxicity tests with Daphnia magna. In the first part of the work, the conditions for the use of LDH activity in toxicity tests with juveniles and adults of D. magna, were optimized. The influence of parameters such as the number of animals per sample, nutritional status, age and the presence of eggs in the brood chamber were investigated. In the second part of the study, both in vivo and in vitro tests based on the alteration of LDH activity of D. magna were developed and tested using zinc chloride as test substance. The results obtained indicate that LDH activity of D. magna may be used as an indicative parameter in aquatic toxicity tests.

Age Factors↗
PubMed2001

Use of Japanese medaka (Oryzias latipes) and Tilapia (Oreochromis mossambicus) in toxicity tests on different industrial effluents in Taiwan.

In Taiwan, aquatic toxicity tests for industrial effluents are not required for discharge permits. However, relying on traditional chemical and physical characteristics of an effluent to monitor and regulate such discharges to manage water quality of a receiving water is insufficient. In this study, we used two fish species, Japanese medaka (Oryzias latipes) and tilapia (Oreochromis mossambicus), and three toxic endpoints, including acute and subacute toxicity, to determine toxicity of seven different types of industrial effluents. Prior to the study, two reference toxicants were tested on two fish species. The LC50s of CdCl2 for tilapia and medaka juveniles were 29.6 +/- 15.3 mg/L and 2.2 +/- 1.2 mg/L, respectively. The sensitivity of medaka embryo mortality and hatching inhibition to CdCl2 were about the same, with the LC50 and EC50 of 0.3 +/- 0.1 mg/L and 0.1 +/- 0.1 mg/L, respectively. The LC50s for tilapia and medaka juveniles to sodium dodecyl sulfate (SDS) were 19.7 +/- 10.6 mg/L and 12.5 +/- 5.9 mg/L. The medaka embryo was less sensitive to SDS than to CdCl2. The embryo's LC50 for SDS was 5.8 +/- 2.8 mg/L and the hatching inhibition EC50 was 1.3 +/- 1.1 mg/L. Results of toxicity tests on different effluents showed that the electroplating effluent was the most toxic, followed by acrylonitrile manufacturing and pulp/paper mill discharges. The LC50s of the electroplating effluent to different assays were in the range of several percents of the whole effluent. The pulp/paper effluent was toxic only to the medaka embryo. The rest of the industrial effluents tested showed either moderate or no toxicity to the animals.

Animals↗