As experience is gained with toxicology testing and as new assays and technologies are developed, it is critical for stakeholders to discuss opportunities to advance our overall testing strategies. To facilitate these discussions, a workshop on practices for assessing immunotoxicity for environmental chemicals was held with the goal of sharing perspectives on immunotoxicity testing strategies and experiences, developmental immunotoxicity (DIT), and integrated and alternative approaches to immunotoxicity testing. Experiences across the chemical and pharmaceutical industries suggested that standard toxicity studies, combined with triggered-based testing approaches, represent an effective and efficient approach to evaluate immunotoxic potential. Additionally, discussions on study design, critical windows, and new guideline approaches and experiences identified important factors to consider before initiating DIT evaluations including assay choice and timing and the impact of existing adult data. Participants agreed that integrating endpoints into standard repeat-dose studies should be considered for fulfilling any immunotoxicity testing requirements, while also maximizing information and reducing animal use. Participants also acknowledged that in vitro evaluation of immunosuppression is complex and may require the use of multiple assays that are still being developed. These workshop discussions should contribute to developing an effective but more resource and animal efficient approach for evaluating chemical immunotoxicity.
This study establishes the reponsiveness of mice bearing the Madison 109 lung carcinoma (M109)1, a tumor relatively resistant to chemotherapy, to the immunomodulator maleic vinyl ether (MVE-2; molecular weight 15,500). BALB/c mice inoculated with 5 × 105 M109 cells into the hind footpad developed a primary tumor which metastasized to the lung within 7 days and resulted in death of the host between 36 and 42 days. Early in the disease, weekly intratumor (i.t.) or intravenous administration of MVE-2 (25 mg/kg) inhibited the growth of the primary tumor and significantly prolonged the life span of the host. During the pulmonary metastatic process, systemic administration of MVE-2 alone or MVE-2 coupled with surgical excision or radiotherapy of the primary tumor became decreasingly efficacious. Late in the disease only MVE-2 introduced directly into the metastatic tumor bed by intra-pleural injection proved to be effective in prolonging life span. These studies indicate that both the primary and metastatic M109 tumors are sensitive to MVE-2 and suggest that the efficacy of MVE-2 treatment is largely dependent upon its distribution in the tumor-bearing mice.
The mouse IgE test is a novel method for the prospective identification of chemicals that have the potential to cause allergic sensitization of the respiratory tract. Activity is measured as a function of increases in the concentration of total serum IgE induced by topical exposure of mice to chemicals; those chemicals that elicit a substantial elevation in IgE are classified as respiratory allergens. The present investigations were designed to evaluate further the utility of the mouse IgE test. For this purpose theassay was conducted in each of fiveindependent laboratories using trimellitic anhydride (TMA), a known cause of respiratory sensitization and occupational asthma, and 2,4-dinitrochlorobenzene (DNCB), a potent contact allergen that is considered not to cause sensitization of the respiratory tract. For these investigations BALB/c mice were used, which are currently the strain of choice for the mouse IgE test. In four of five laboratories, exposure of mice to TMA caused a statistically significant increase in the serum concentration of IgE. Under the same conditions of exposure, DNCB failed in all laboratories to induce a significant change in IgE levels compared with vehicle-treated controls. In three of five laboratories, the concentration of total serum IgE was greater in TMA- than in DNCB-treated mice. The concentration of IgE in the sera of mice exposed to vehicle alone was not significantly different from that found in untreated (naive)animals. Although thedifferential ability, in some instances, of TMA and DNCB to provoke increases in serum IgE is consistent with the results of previous investigations, it was found in all five laboratories that there existed considerable variation among individual mice within experimental groups with respect to IgE levels. These data mirrored an increasing variability in serum IgE concentrations among BALB/c strain mice found in one of the participating laboratories. For this reason mice of another strain (C57BL/6) were evaluated in the mouse IgE test by the same laboratory. The data presented here reveal that C57BL/6 mice display more stable serum IgE levels and a lower constitutive level of serum IgE but nevertheless exhibit differential responses to TMA and DNCB, with only the former causing a substantial increase in IgE concentrations. Collectively these results suggest that although the mouse IgE test continues to show some promise as an approach to the identification of chemical respiratory allergens, there is a need for careful consideration of thestrain of mouseused beforetheassay can be considered fully optimized.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
