Identifying an indoor air exposure limit for formaldehyde considering both irritation and cancer hazards

Formaldehyde is a well-studied chemical and effects from inhalation exposures have been extensively characterized in numerous controlled studies with human volunteers, including asthmatics and other sensitive individuals, which provide a rich database on exposure concentrations that can reliably produce the symptoms of sensory irritation. Although individuals can differ in their sensitivity to odor and eye irritation, the majority of authoritative reviews of the formaldehyde literature have concluded that an air concentration of 0.3 ppm will provide protection from eye irritation for virtually everyone. A weight of evidence-based formaldehyde exposure limit of 0.1 ppm (100 ppb) is recommended as an indoor air level for all individuals for odor detection and sensory irritation. It has recently been suggested by the International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), and the US Environmental Protection Agency (US EPA) that formaldehyde is causally associated with nasopharyngeal cancer (NPC) and leukemia. This has led US EPA to conclude that irritation is not the most sensitive toxic endpoint and that carcinogenicity should dictate how to establish exposure limits for formaldehyde. In this review, a number of lines of reasoning and substantial scientific evidence are described and discussed, which leads to a conclusion that neither point of contact nor systemic effects of any type, including NPC or leukemia, are causally associated with exposure to formaldehyde. This conclusion supports the view that the equivocal epidemiology studies that suggest otherwise are almost certainly flawed by identified or yet to be unidentified confounding variables. Thus, this assessment concludes that a formaldehyde indoor air limit of 0.1 ppm should protect even particularly susceptible individuals from both irritation effects and any potential cancer hazard

Keratinocytes and cytokine/growth factors

Cytokines are polypeptide growth factors produced by most nucleated cells in the body including epithelial cells, keratinocytes, and Langerhans cells in the skin. Cytokines can be classified into interleukins, tumor necrosis factors, chemokines, colony-stimulating factor interferons, and growth factors. Like classic hormones, cytokines bind to specific receptors to transmit their messages to target cells. Cytokine receptors can be divided into three cytokine receptor superfamilies, the immunoglobulin superfamily, the hematopoietin family, and the tumor necrosis factor family. Following cytokine/cytokine-receptor binding (first messenger), a signal transduction pathway is initiated. Factors affecting homeostasis in the skin and oral mucosa include a delicate balance between cytokines/cytokine-receptors and their antagonists. An imbalance in these variables can influence the development of cutaneous and oral diseases-such as lichen planus, autoimmune disorders, and some neoplastic processes-and can affect wound healing. Potential uses of cytokines include cancer and antiviral therapy

Urokinase plasminogen activator mRNA is induced by IL-1α and TNF-α in in vitro acantholysis

The role of urokinase type plasminogen activator (uPA) has been well documented in the pathogenesis of pemphigus vulgaris (PV). Activation of plasminogen into active serine protease plasmin initiates extracellular proteolysis leading to acantholysis but the mechanisms underlying this process are not clearly understood. We have previously shown that keratinocyte derived cytokines IL-1α and TNF-α are involved in PV-induced acantholysis. In the present study we sought to examine whether keratinocyte-derived IL-1α and TNF-α are correlated with uPA induction in keratinocytes during acantholysis. Normal human keratinocytes were incubated with diluted PV serum. mRNAs for IL-1α, TNF-α and uPA were examined with RT-PCR at various time points and acantholysis was measured. IL-1α, TNF-α and uPA mRNAs were all induced in keratinocytes following PV serum stimulation; IL-1α/TNF-α mRNAs' expression was earlier than the expression of uPA mRNA. To further examine the role of IL-1α, TNF-α and uPA in acantholysis, we performed antibody blocking studies. Anti-IL-la, anti-TNF-a and anti-uPA antibodies suppressed acantholysis by 76%, 80% and 90%, respectively. In addition, anti-IL-1α and anti-TNF-α antibodies inhibited uPA mRNA induction, whereas anti-uPA antibodies did not alter IL-1α/TNF-α mRNAs' expression. Our results confirm the role of uPA in acantholysis and suggest an involvement of IL-1α/TNF-α in uPA induction. © Blackwell Munksgaard, 2003

Rethinking the role of tumour necrosis factor-α in ultraviolet (UV) B-induced immunosuppression: Altered immune response in UV-irradiated TNFR1R2 gene-targeted mutant mice

Background: Ultraviolet (UV) B-induced immunosuppression, implicated in the pathogenesis of skin cancers, is postulated to be mediated in part by cis-urocanic acid (cis-UCA) via tumour necrosis factor (TNF)-alpha;. TNF-α produces morphological changes in Langerhans cells indistinguishable from those induced by UVB exposure and antibodies against TNF-α have been demonstrated to inhibit UVB-induced immunosuppression in vivo. Objectives: To clarify further the role of TNF-α in UVB-induced immunosuppression and in cis-UCA immunosuppression. Methods: We performed a contact hypersensitivity (CHS) assay on gene-targeted mutant mice (TNFR1R2-/-) lacking genes for both receptors (p55 and p75) for TNF-α. Mice were either irradiated with UVB or injected intradermally with cis-UCA, sensitized with 2,4-dinitrofluoro-benzene, challenged on the ears and the response was measured. Results: The TNFR1R2-/- mice showed hyporesponsiveness in the CHS response compared with wild-type (P lt; 0.001), confirming the proinflammatory role of TNF-α. However, significant suppression of CHS was seen after irradiation and after cis-UCA injection in both locally (sensitization on irradiated site; P < 0.05) and systemically (sensitization on non-irradiated site; P < 0.05) sensitized wild-type and gene-targeted mice. Conclusions: These results demonstrate that TNF-α signalling is only partially involved in UVB-induced immunosuppression and does not play a major part in the cis-UCA immunosuppression mechanism

Immune modulation in pemphigus vulgaris: Role of CD28 and IL-10

Pemphigus vulgaris (PV) is an autoimmune bullous skin disease characterized by Abs to the desmosomal cadherin desmoglein-3. Although the autoantibodies have been shown to be pathogenic, the role of the cellular immune system in the pathology of pemphigus-induced acantholysis is unclear. To further delineate the potential role of T cell-signaling pathways in the pathogenesis of PV, we performed passive transfer experiments with PV IgG in gene-targeted mutant mice. Our results demonstrated that CD28-deficient mice (lacking a costimulatory signal for T cell activation) are 5-fold more sensitive to the development of PV than wild-type mice. To evaluate whether the higher incidence of disease was due to an impairment in intercellular adhesion of keratinocytes, we performed an in vitro acantholysis, using CD28(-/-) mice keratinocytes. No alteration in in vitro adhesion was detected in CD28(-/-)-type keratinocytes. Because the CD28 molecule plays a pivotal role in the induction of Th2 cytokines, we examined the levels of a prototypic Th2 cytokine (IL-10) in CD28(-/-) mice. Lower levels of IL-10 mRNA were found in lesions from CD28(-/-) mice. To determine whether pemphigus susceptibility in CD28(-/-) was related to IL-10 deficiency, we performed passive transfer experiments in IL-10(-/-) mice that demonstrated increased blisters compared with controls. To confirm that IL-10 is involved in the pathogenesis, rIL-10 was given with PV IgG. IL-10 significantly suppressed the disease activity. These data suggest a potential role of IL-10 in PV

Immune modulation in pemphigus vulgaris: Role of CD28 and IL-10

Pemphigus vulgaris (PV) is an autoimmune bullous skin disease characterized by Abs to the desmosomal cadherin desmoglein-3. Although the autoantibodies have been shown to be pathogenic, the role of the cellular immune system in the pathology of pemphigus-induced acantholysis is unclear. To further delineate the potential role of T cell-signaling pathways in the pathogenesis of PV, we performed passive transfer experiments with PV IgG in gene-targeted mutant mice. Our results demonstrated that CD28-deficient mice (lacking a costimulatory signal for T cell activation) are 5-fold more sensitive to the development of PV than wild-type mice. To evaluate whether the higher incidence of disease was due to an impairment in intercellular adhesion of keratinocytes, we performed an in vitro acantholysis, using CD28(-/-) mice keratinocytes. No alteration in in vitro adhesion was detected in CD28(-/-)-type keratinocytes. Because the CD28 molecule plays a pivotal role in the induction of Th2 cytokines, we examined the levels of a prototypic Th2 cytokine (IL-10) in CD28(-/-) mice. Lower levels of IL-10 mRNA were found in lesions from CD28(-/-) mice. To determine whether pemphigus susceptibility in CD28(-/-) was related to IL-10 deficiency, we performed passive transfer experiments in IL-10(-/-) mice that demonstrated increased blisters compared with controls. To confirm that IL-10 is involved in the pathogenesis, rIL-10 was given with PV IgG. IL-10 significantly suppressed the disease activity. These data suggest a potential role of IL-10 in PV

Enhanced epidermal langerhans cell migration in IL-10 knockout mice

The migration of epidermal Langerhans cells (LC) to lymph nodes (LN) is critical in the initiation of contact hypersensitivity (CHS) responses. Studies suggest that contact allergen-induced epidermal proinflammatory cytokines, including IL-1 and TNF-α, play important roles in promoting LC migration. Contact allergens also induce epidermal anti-inflammatory cytokines such as IL-10. Since IL-10 down-regulates proinflammatory cytokine production and inhibits CHS, we hypothesized that IL-10 might inhibit LC migration. To test this hypothesis, IL-10 knockout (KO) mice were epicutaneously sensitized with the hapten, FITC, and 24 h later hapten- bearing cells in the draining LN were examined. The number of hapten-bearing cells in the LN was significantly greater in IL-10 KO mice than in wild-type mice. The mutant mice also had an exaggerated CHS to FITC. Pretreatment with anti-TNF-α Ab or IL-1R antagonist significantly reduced the number of hapten-bearing cells in the LN, suggesting that IL-10 modulation of LC migration involves IL-1 and TNF-α. Moreover, IL-10 KO mice demonstrated a greater increase in TNF-α, IL-1α, and IL-1β mRNAs in the allergen-exposed epidermis, and keratinocytes derived from the mutant mice were able to produce higher amounts of TNF-α and IL-1α protein. These data suggest that IL-10 plays an inhibitory role in LC migration and that this effect may occur via the down-regulation of TNF-α and IL-1 production