Can someone decifer these two reports for me?

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Hi All,

May I ask you all a favor? Here are two different outcomes from rodent studies. Could you all help me understand these?

Sharon

Comparison of Inflammatory and Cytotoxic Lung Responses in Mice after Intratracheal Exposure to Spores of Two Different Stachybotrys chartarum Strains J. Flemming, B. Hudson and T. G. Rand1

Department of Biology, Saint ’s University, 923 Robie St., Halifax, Nova Scotia, Canada B3H 3C3

Received July 7, 2003; accepted December 11, 2003 Stachybotrys chartarum is an important toxigenic fungus that has been associated with respiratory disease onset in animals and humans. While it can be separated into macrocyclic trichothecene- and atranone-producing chemotypes based on secondary metabolite production, effects of spores of the two chemotypes on lungs are poorly understood. In this study we used bronchoalveolar lavage fluid (BALF) to investigate dose-response (30, 300, 3000 spores/g body weight [bW]) and time-course (3, 6, 24, 48, 96 h post instillation [PI]) relationships in mice to exposure of macrocyclic trichothecene- (JS 58-17) and atranone-producing (JS 58-06) S. chartarum strains, as well as Cladosporium cladosporioides spores. BALF total protein, albumin, pro-inflammatory cytokine (IL-1ß, IL-6, and tumor necrosis factor- [TNF-]), and lactate dehydrogenase (LDH) concentrations showed significant (p < 0.05) fungal species (S. chartarum vs. C. cladosporioides) and strain (58-17 vs. 58-06), spore dose and time dependent changes. The no adverse effect level (NOAEL) due to exposure to spores of JS 58-17 and JS 58-06 was < 30 spores/g BW; for C. cladosporioides it was < 300 spores/g BW. At moderate and high S. chartarum doses, BALF composition reflects differences in strain toxicity while at the lowest dose, BALF composition of either S. chartarum strain were similar. This suggests that at low spore doses, it is spore sequestered factors common to both strains not strain dependent toxins that are contributing to lung disease onset.

Key Words: Stachybotrys chartarum; spores; inflammation; cytotoxicity; macrocyclic trichothecenes; atranones; intratracheal instillation; mouse.

Here is another one:

Experimental data on the in vivo toxicity of mycotoxins are scant. Frequently cited are the inhalation LC50 values determined for mice, rats, and guinea pigs exposed for 10 minutes to T-2 toxin, a trichothecene mycotoxin produced by Fusarium spp.74,75 Rats were most sensitive in these studies, but there was no mortality in rats exposed to 1.0 mg T-2 toxin/m3. No data were found on T-2 concentrations in Fusarium spores, but another trichothecene, satratoxin H, has been reported at a concentration of 1.0 x 10-4 ng/spore in a “highly toxic†S. chartarum strain s. 72.31 To provide perspective relative to T-2 toxin, 1.0 mg satratoxin H/m3 air would require 1010 (ten billion) of these s. 72 S. chartarum spores/m3. In single-dose in vivo studies, S. chartarum spores have been administered intranasally to mice31 or intratracheally to rats.76,77 High doses (30 x 106 spores/kg and higher) produced pulmonary inflammation and hemorrhage in both species. A range of doses were administered in the rat studies and multiple, sensitive indices of effect were monitored, demonstrating a graded dose response with 3 x 106 spores/kg being a clear no-effect dose. Airborne S. chartarum spore concentrations that would deliver a comparable dose of spores can be estimated by assuming that all inhaled spores are retained and using standard default values for human subpopulations of particular interest78 – very small infants,† school-age children,†† and adults.††† The no-effect dose in rats (3 x 106 spores/kg) corresponds to continuous 24-hour exposure to 2.1 x 106 spores/m3 for infants, 6.6 x 106 spores/m3 for a school-age child, or 15.3 x 106 spores/m3 for an adult. That calculation clearly overestimates risk because it ignores the impact of dose rate by implicitly assuming that the acute toxic effects are the same whether a dose is delivered as a bolus intratracheal instillation or gradually over 24 hours of inhalation exposure. In fact, a cumulative dose delivered over a period of hours, days, or weeks is expected to be less acutely toxic than a bolus dose, which would overwhelm detoxification systems and lung clearance mechanisms. If the no-effect 3 x 106 spores/kg intratracheal bolus dose in rats is regarded as a 1-minute administration (3 x 106 spores/kg/min), achieving the same dose rate in humans (using the same default assumptions as previously) would require airborne concentrations of 3.0 x 109 spores/m3 for an infant, 9.5 x 109 spores/m3 for a child, or 22.0 x 109 spores/m3 for an adult. In a repeat-dose study, mice were given intranasal treatments twice weekly for three weeks with “highly toxic†s. 72 S. chartarum spores at doses of 4.6 x 106 or 4.6 x 104 spores/kg (cumulative doses over three weeks of 2.8 x 107 or 2.8 x 105 spores/kg).79 The higher dose caused severe inflammation with hemorrhage, while less severe inflammation, but no hemorrhage was seen at the lower dose of s. 72 spores. Using the same assumptions as previously (and again ignoring dose-rate implications), airborne S. chartarum spore concentrations that would deliver the non-hemorrhagic cumulative three-week dose of 2.8 x 105 spores/kg can be estimated as 9.4 x 103 spores/m3 for infants, 29.3 x 103 spores/m3 for a school-age child, and 68.0 x 103 spores/m3 for adults (assuming exposure for 24 hours per day, 7 days per week, and 100% retention of spores). The preceding calculations suggest lower bound estimates of airborne S. chartarum spore concentrations corresponding to essentially no-effect acute and subchronic exposures. Those concentrations are not infeasible, but they are improbable and inconsistent with reported spore concentrations. For example, in data from 9,619 indoor air samples from 1,717 buildings, when S. chartarum was detected in indoor air (6% of the buildings surveyed) the median airborne concentration was 12 CFU/m3 (95% CI 12 to 118 CFU/m3).80