Toxicological assessment of tridecafluorohexylethyl methacrylate (6:2 FTMAC).

The toxicity of tridecafluorohexylethyl methacrylate (6:2 FTMAC), an acrylic monomer used in producing polymeric substances, was evaluated. 6:2 FTMAC has low acute oral and dermal toxicity (LD50>5000 mg/kg), was not a skin or eye irritant, and did not demonstrate skin sensitization potential in a local lymph node assay (LLNA). 6:2 FTMAC was not mutagenic in the bacterial reverse mutation (Ames) test or in the mouse lymphoma assay. 6:2 FTMAC induced structural aberrations in human peripheral blood lymphocytes in vitro in the absence of metabolic activation but not in the presence of S9 metabolic activation. No numerical aberrations were detected under any testing condition. Also, no increase occurred in structural or numerical chromosomal aberrations in an in vivo mouse micronucleus assay in 6:2 FTMAC treated animals compared to controls. 6:2 FTMAC was administered at 0, 100, 500 and 1000 mg/kg/day via gavage to male and female SD rats for 14 days. No test substance-related effects on mortality, clinical signs, body weights, nutritional parameters, or clinical pathology were observed at any dose. Test substance-related increases in liver weights in males and females at all dose levels and thyroid and kidney weights in 500 and 1000 mg/kg/day males were noted. While there was no histopathological correlate for thyroid and kidney weight changes, minimal hypertrophy was noted in liver in males and females at 1000 mg/kg/day group. The changes noted in teeth (altered mineralization; retention of basophilic material) and femur (increased mineralization) in all treated groups were not associated with clinical signs or microscopic changes and were likely related to free fluoride formed from 6:2 FTMAC metabolism. Plasma (3-4-fold) and urine (30-50-fold) fluoride was higher in treated groups versus controls. Therefore, the changes noted in organ weights, teeth, femur, plasma or urine were not considered adverse. In the repeated dose toxicity study, the no-observed-adverse-effect-level (NOAEL) was 1000 mg/kg/day. Based on mean measured concentrations, the 96-h LC50 in fathead minnow was >14.5 mg/L and the 72-h EC50 in Pseudokirchneriella subcapitata was >24.6 mg/L, while the 48-h EC50 in Daphnia magna, based on nominal concentrations, was >120 mg/L. Overall, 6:2 FTMAC is considered to have low toxicity potential based on these studies.

HLA mismatch direction in cord blood transplantation: impact on outcome and implications for cord blood unit selection.

Donor-recipient human leukocyte antigen mismatch level affects the outcome of unrelated cord blood (CB) transplantation. To identify possible "permissive" mismatches, we examined the relationship between direction of human leukocyte antigen mismatch ("vector") and transplantation outcomes in 1202 recipients of single CB units from the New York Blood Center National Cord Blood Program treated in United States Centers from 1993-2006. Altogether, 98 donor/patient pairs had only unidirectional mismatches: 58 in the graft-versus-host (GVH) direction only (GVH-O) and 40 in the host-versus-graft or rejection direction only (R-O). Engraftment was faster in patients with GVH-O mismatches compared with those with 1 bidirectional mismatch (hazard ratio [HR] = 1.6, P = .003). In addition, patients with hematologic malignancies given GVH-O grafts had lower transplantation-related mortality (HR = 0.5, P = .062), overall mortality (HR = 0.5, P = .019), and treatment failure (HR = 0.5, P = .016), resulting in outcomes similar to those of matched CB grafts. In contrast, R-O mismatches had slower engraftment, higher graft failure, and higher relapse rates (HR = 2.4, P = .010). Based on our findings, CB search algorithms should be modified to identify unidirectional mismatches. We recommend that transplant centers give priority to GVH-O-mismatched units over other mismatches and avoid selecting R-O mismatches, if possible.

E. coli Lipopolysaccharide: acute oral toxicity study in mice.

A single dose of endotoxin (lipopolysaccharide) from a common laboratory cloning and expression strain (Escherichia coli BL21[DE3]) was administered to groups of male and female CD-1 mice (n=5/group) at doses up to 1,000,000 endotoxin units (EU) per mouse by oral gavage. The mice were observed for mortality, body weight effects, and clinical signs for 14 days after which they were sacrificed for gross organ necropsy. All mice survived until the scheduled sacrifice, no clinical signs of toxicity were observed, no test substance-related body weight losses occurred and no gross lesions were present at necropsy. Under the conditions of this study, oral administration of E. coli BL21(DE3) endotoxin to mice at a dose of up to 1,000,000 EU/mouse produced no evidence of toxicity.

Reexposure of cord blood to noninherited maternal HLA antigens improves transplant outcome in hematological malignancies.

Cord blood (CB) hematopoietic stem cell transplantation can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result from tolerance-inducing events during pregnancy but to date this concept has not been tested in CB transplantation. Hence we analyzed the impact of fetal exposure to noninherited maternal antigens (NIMA) of the HLA-A, -B antigens, or -DRB1 alleles on the outcome of CB transplants. The 1,121 patients studied were transplanted for hematological malignancy with a single CB unit: 1,059 received grafts mismatched for one or two HLA antigens. Of these patients, 79 patients had a mismatched antigen that was identical to a donor NIMA, 25 with one HLA mismatch (MM), and 54 with two. If there was a NIMA match, transplant-related mortality (TRM) was improved, especially in patients >or=10 years (P = 0.012) as were overall mortality and treatment failure (P = 0.022 and 0.020, respectively, in the older subset), perhaps related to improved neutrophil recovery, especially in patients who received a low total nucleated cell (TNC) dose (P = 0.031). Posttransplant relapse rate also tended to be reduced, especially in patients with myelogenous malignancies given units with a single HLA mismatch (P = 0.074). These findings represent unique evidence that donor exposure to NIMA can improve survival in unrelated CB transplantation and might reduce relapse, indicating that cord blood cells can mount an antileukemic effect. By matching for donor NIMAs in search algorithms of CB inventories, the probability of selecting a graft with an optimal outcome will increase significantly.