Building and environmental factors that influence bacterial and fungal loading on air conditioning cooling coils.

We investigated bacterial and fungal concentrations on cooling coils of commercial AC units and quantified associations between microbial loads and AC unit or building operational parameters. A field campaign was conducted to sample 25 AC units in the humid, subtropical climate of Southern CT, USA and 15 AC units in the hot-summer Mediterranean climate of Sacramento, CA, USA. Median concentrations (with interquartile range) of bacteria and fungi on the cooling coils were 1.2 × 107 (5.1 × 106 -3.9 × 107 ) cells/m2 and 7.6 × 105 (5.6 × 104 -4.4 × 106 ) spore equivalents (SE)/m2 , respectively. Concentrations varied among units with median unit concentrations ranging three orders of magnitude for bacteria and seven orders of magnitude for fungi. Controlled comparisons and multivariable regressions indicate that dominant factors associated with AC coil loading include the nominal efficiency of upstream filters (P = .008 for bacteria and P < .001 for fungi) and coil moisture, which was reflected in fungal loading differences between top and bottom halves of the AC coils in Southern CT (P = .05) and the dew points of the two climates considered (P = .04). Environmental and building characteristics explained 42% (P < .001) of bacterial concentration variability and 66% (P < .001) of fungal concentration variability among samples.

Current perspective on actinic keratosis: a review.

Actinic keratoses (AKs) are common, with prevalence in the U.S.A. estimated at almost 40 million in 2004 and annual costs of > $1 billion (U.S.D.). However, there is no universally accepted definition of AK and thus it is difficult to identify reliably. AKs are lesions of epidermal keratinocytic dysplasia that result from chronic sun exposure and have the ability to progress to invasive squamous cell carcinoma (SCC), but clinicians disagree about whether AKs are premalignant lesions, superficial SCCin situ or epiphenomena of chronically sun-damaged skin. Yearly AK to SCC progression rates of 0·6% were reported in an elderly population with multiple prior keratinocyte carcinomas (KCs); and rates of spontaneous AK regression have been reported to be > 50%, but regressed lesions often reappear. As AKs have both cosmetic consequences and potential for malignant transformation, there are multiple reasons for treatment. There is no current agreement on the most efficacious treatment, but 5-fluorouracil has been shown to both prevent and treat AKs, and imiquimod and photodynamic therapy may have the best cosmetic outcomes. AKs may be treated to improve appearance and relieve symptoms, but the keratinocytic dysplasia that gives rise to malignancy, and sometimes appears as an AK, may be what actually threatens patient health. Thus, treatments should aim to decrease the risk of KC or facilitate KC diagnosis by reducing the potential for misidentification created when a KC appears in a field of AKs. Improved agreement among clinicians on AK definition may improve management.

Quantitative filter forensics for indoor particle sampling.

Filter forensics is a promising indoor air investigation technique involving the analysis of dust which has collected on filters in central forced-air heating, ventilation, and air conditioning (HVAC) or portable systems to determine the presence of indoor particle-bound contaminants. In this study, we summarize past filter forensics research to explore what it reveals about the sampling technique and the indoor environment. There are 60 investigations in the literature that have used this sampling technique for a variety of biotic and abiotic contaminants. Many studies identified differences between contaminant concentrations in different buildings using this technique. Based on this literature review, we identified a lack of quantification as a gap in the past literature. Accordingly, we propose an approach to quantitatively link contaminants extracted from HVAC filter dust to time-averaged integrated air concentrations. This quantitative filter forensics approach has great potential to measure indoor air concentrations of a wide variety of particle-bound contaminants. Future studies directly comparing quantitative filter forensics to alternative sampling techniques are required to fully assess this approach, but analysis of past research suggests the enormous possibility of this approach.

Primary and secondary consequences of indoor air cleaners.

Air cleaning is broadly applied to reduce contaminant concentrations in many buildings. Although diverse in underlying technology, mode of application, target contaminants, and effectiveness, there are also commonalities in the framework for understanding their primary impact (i.e. concentration reductions) and secondary impacts (e.g. energy use and by-product production). Furthermore, both primary and secondary impacts are moderated by the specific indoor context in which an air cleaner is used. This investigation explores the dynamics of removal efficiency in a variety of air cleaners and combines efficiency and flow rate to put air cleaning in the context of real indoor environments. This allows for the direct comparison to other indoor pollutant loss mechanisms (ventilation and deposition) and further suggests that effective air cleaner use is context and contaminant specific. The concentration reduction impacts of air cleaning need to be contrasted with the secondary consequences that arise from the use of air cleaners. This study emphasizes two important secondary consequences: energy use of the air cleaning process and primary and secondary emissions from air cleaners. This study also identifies current research challenges and areas for large leaps in our understanding of the role of air cleaners in improving indoor environmental quality.

Particulate reactive oxygen species on total suspended particles - measurements in residences in Austin, Texas.

The biologically relevant characteristics of particulate matter (PM) in homes are important to assessing human health. The concentration of particulate reactive oxygen species (ROS) was assessed in eight homes and was found to be lower inside (mean ± s.e. = 1.59 ± 0.33 nmol/m3 ) than outside (2.35 ± 0.57 nmol/m3 ). Indoor particulate ROS concentrations were substantial and a major fraction of indoor particulate ROS existed on PM2.5 (58 ± 10%), which is important from a health perspective as PM2.5 can carry ROS deep into the lungs. No obvious relationships were evident between selected building characteristics and indoor particulate ROS concentrations, but this observation would need to be verified by larger, controlled studies. Controlled experiments conducted at a test house suggest that indoor ozone and terpene concentrations substantially influence indoor particulate ROS concentrations when outdoor ozone concentrations are low, but have a weaker influence on indoor particulate ROS concentrations when outdoor ozone concentrations are high. The combination of substantial indoor concentrations and the time spent indoors suggest that further work is warranted to assess the key parameters that drive indoor particulate ROS concentrations.

Characterizing the bacterial communities in retail stores in the United States.

The microorganisms present in retail environments have not been studied in detail despite the fact that these environments represent a potentially important location for exposure. In this study, HVAC filter dust samples in 13 US retail stores were collected and analyzed via pyrosequencing to characterize the indoor bacterial communities and to explore potential relationships between these communities and building and environmental parameters. Although retail stores contained a diverse bacterial community of 788 unique genera, over half of the nearly 118K sequences were attributed to the Proteobacteria phylum. Streptophyta, Bacillus, Corynebacterium, Pseudomonas, and Acinetobacter were the most prevalent genera detected. The recovered indoor airborne microbial community was statistically associated with both human oral and skin microbiota, indicating occupants are important contributors, despite a relatively low occupant density per unit volume in retail stores. Bacteria generally associated with outdoor environments were present in the indoor communities with no obvious association with air exchange rate, even when considering relative abundance. No significant association was observed between the indoor bacterial community recovered and store location, store type, or season. However, predictive functional gene profiling showed significant associations between the indoor community and season. The microbiome recovered from multiple samples collected months apart from the same building varied significantly indicating that caution is warranted when trying to characterize the bacterial community with a single sampling event.

Semi-volatile organic compounds in heating, ventilation, and air-conditioning filter dust in retail stores.

Retail stores contain a wide range of products that can emit a variety of indoor pollutants. Among these chemicals, phthalate esters and polybrominated diphenyl ethers (PBDEs) are two important categories of semi-volatile organic compounds (SVOCs). Filters in heating, ventilation, and air-conditioning (HVAC) system collect particles from large volumes of air and thus potentially provide spatially and temporally integrated SVOC concentrations. This study measured six phthalate and 14 PBDE compounds in HVAC filter dust in 14 retail stores in Texas and Pennsylvania, United States. Phthalates and PBDEs were widely found in the HVAC filter dust in retail environment, indicating that they are ubiquitous indoor pollutants. The potential co-occurrence of phthalates and PBDEs was not strong, suggesting that their indoor sources are diverse. The levels of phthalates and PBDEs measured in HVAC filter dust are comparable to concentrations found in previous investigations of settled dust in residential buildings. Significant correlations between indoor air and filter dust concentrations were found for diethyl phthalate, di-n-butyl phthalate, and benzyl butyl phthalate. Reasonable agreement between measurements and an equilibrium model to describe SVOC partitioning between dust and gas-phase is achieved.

Volatile organic compounds in fourteen U.S. retail stores.

Retail buildings have a potential for both short-term (customer) and long-term (occupational) exposure to indoor pollutants. However, little is known about volatile organic compound (VOC) concentrations in the retail sector and influencing factors, such as ventilation, in-store activities, and store type. We measured VOC concentrations and ventilation rates in 14 retail stores in Texas and Pennsylvania. With the exception of formaldehyde and acetaldehyde, VOCs were present in retail stores at concentrations well below health guidelines. Indoor formaldehyde concentrations ranged from 4.6 ppb to 67 ppb. The two mid-sized grocery stores in the sample had the highest levels of ethanol and acetaldehyde, with concentrations up to 2.6 ppm and 92 ppb, respectively, possibly due to the preparation of dough and baking activities. Indoor-to-outdoor concentration ratios indicated that indoor sources were the main contributors to indoor VOC concentrations for the majority of compounds. There was no strong correlation between ventilation and VOC concentrations across all stores. However, increasing the air exchange rates at two stores led to lower indoor VOC concentrations, suggesting that ventilation can be used to reduce concentrations for some specific stores.

Ultrafine particle removal by residential heating, ventilating, and air-conditioning filters.

This work uses an in situ filter test method to measure the size-resolved removal efficiency of indoor-generated ultrafine particles (approximately 7-100 nm) for six new commercially available filters installed in a recirculating heating, ventilating, and air-conditioning (HVAC) system in an unoccupied test house. The fibrous HVAC filters were previously rated by the manufacturers according to ASHRAE Standard 52.2 and ranged from shallow (2.5 cm) fiberglass panel filters (MERV 4) to deep-bed (12.7 cm) electrostatically charged synthetic media filters (MERV 16). Measured removal efficiency ranged from 0 to 10% for most ultrafine particles (UFP) sizes with the lowest rated filters (MERV 4 and 6) to 60-80% for most UFP sizes with the highest rated filter (MERV 16). The deeper bed filters generally achieved higher removal efficiencies than the panel filters, while maintaining a low pressure drop and higher airflow rate in the operating HVAC system. Assuming constant efficiency, a modeling effort using these measured values for new filters and other inputs from real buildings shows that MERV 13-16 filters could reduce the indoor proportion of outdoor UFPs (in the absence of indoor sources) by as much as a factor of 2-3 in a typical single-family residence relative to the lowest efficiency filters, depending in part on particle size.

Penetration of ambient submicron particles into single-family residences and associations with building characteristics.

UNLABELLED: This work improves knowledge of particle penetration into buildings by (i) refining a particle penetration test method that minimizes the duration and invasiveness required by individual tests without sacrificing accuracy, (ii) applying the method in an unoccupied manufactured test house and 18 single-family homes in Austin, Texas, USA, and (iii) exploring correlations between particle penetration and building characteristics, including results from blower door air leakage tests. The mean (± s.d.) measured penetration factor of submicron particles (20-1000 nm, not size-resolved) was 0.47 ± 0.15 in 19 residences that relied on infiltration for ventilation air, ranging from 0.17 ± 0.03 to 0.72 ± 0.08. Particle penetration factors (P) and outdoor particle source terms (P × air exchange rates) were both significantly and positively correlated with results from blower door air leakage tests. Outdoor particle source terms were also significantly and negatively correlated with the year of construction. These results suggest that occupants of leakier and older homes are exposed to higher indoor concentrations of outdoor submicron particles than those in tighter and newer homes, and that simple air leakage tests may be able to provide an approximate prediction of outdoor particle infiltration into single-family residences. PRACTICAL IMPLICATIONS: Results from this work suggest that knowledge of simple building characteristics (i.e., the year of construction and blower door test results) may be used to predict the ability of outdoor particles to infiltrate into single-family residences, which could facilitate easier estimates of indoor exposures to outdoor particulate matter across the building stock. The methods within can also be extended to other buildings and can be used to assess possible changes in penetration factors because of envelope retrofits. Because outdoor particle size distributions were not measured during this study, these tests should also be repeated with size-resolved particle instrumentation.

Long-term performance of passive materials for removal of ozone from indoor air.

The health effects associated with exposure to ozone range from respiratory irritation to increased mortality. In this paper, we explore the use of three green building materials and an activated carbon (AC) mat that remove ozone from indoor air. We studied the effects of long-term exposure of these materials to real environments on ozone removal capability and pre- and post-ozonation emissions. A field study was completed over a 6-month period, and laboratory testing was intermittently conducted on material samples retrieved from the field. The results show sustained ozone removal for all materials except recycled carpet, with greatest ozone deposition velocity for AC mat (2.5-3.8 m/h) and perlite-based ceiling tile (2.2-3.2 m/h). Carbonyl emission rates were low for AC across all field sites. Painted gypsum wallboard and perlite-based ceiling tile had similar overall emission rates over the 6-month period, while carpet had large initial emission rates of undesirable by-products that decayed rapidly but remained high compared with other materials. This study confirms that AC mats and perlite-based ceiling tile are viable surfaces for inclusion in buildings to remove ozone without generating undesirable by-products. PRACTICAL IMPLICATIONS The use of passive removal materials for ozone control could decrease the need for, or even render unnecessary, active but energy consuming control solutions. In buildings where ozone should be controlled (high outdoor ozone concentrations, sensitive populations), materials specifically designed or selected for removing ozone could be implemented, as long as ozone removal is not associated with large emissions of harmful by-products. We find that activated carbon mats and perlite-based ceiling tiles can provide substantial, long-lasting, ozone control.

The effect of an ion generator on indoor air quality in a residential room.

UNLABELLED: Ion generators charge particles with a corona prior to their removal on collector plates or indoor surfaces and also emit ozone, which can react with terpenes to yield secondary organic aerosol, carbonyls, carboxylic acids, and free radicals. This study characterized the indoor air quality implications of operating an ion generator in a 27 m(3) residential room, with four different test room configurations. Two room configurations had carpet overlaying the original flooring of stained/sealed concrete, and for one configuration with and without carpet, a plug-in air freshener was used as a terpene source. Measurements included airborne sampling of particulate matter (0.015-20 µm), terpenes and C(1) -C(4) and C(6) -C(10) aldehydes, ozone concentrations, and air exchange rates. When the heating, ventilating, and air-conditioning system was not operating (room air exchange rate = ∼0.5/h), the use of the ion generator in the presence of the air freshener led to a net increase in ultrafine particles (<0.1 µm). Also, increased concentrations of ozone were observed regardless of air freshener presence, as well as increases in formaldehyde and nonanal, albeit within measurement uncertainty in some cases. Thus, it may be prudent to limit ion generator use indoors until evidence of safety can be ascertained. PRACTICAL IMPLICATIONS: Portable ion generators are intended to clean the air of particles, but they may emit ozone as a byproduct of their operation, which has the potential to degrade indoor air quality. This study showed that under certain conditions in a residential room, the use of a portable ion generator can increase concentrations of ozone and, to a lesser degree, potentially aldehydes. Also, if operated in the presence of a plug-in air freshener that emits terpenes, its use can increase concentrations of secondary organic aerosol in the ultrafine size range.

Formaldehyde in residences: long-term indoor concentrations and influencing factors.

UNLABELLED: Chronic human exposure to formaldehyde is significantly increased by indoor sources. However, information is lacking on why these exposures appear to persist in older homes with aging sources. We use data from the Relationships of Indoor, Outdoor, and Personal Air study to evaluate 179 residences, most of which were older than 5 years. We assess the dependence of indoor formaldehyde concentrations (C(in)) on building type and age, whole-house air exchange rate, indoor temperature, and seasonal changes. Indoor formaldehyde had mean and median concentrations of 17 ppb, and primarily originated from indoor sources. The factors we analyzed did not explain much of the variance in C(in), probably because of their limited influence on mechanisms that control the long-term release of formaldehyde from aging pressed-wood products bound with urea-formaldehyde (UF) resins. We confirmed that the mitigating effects of ventilation on C(in) decrease with time through the analysis of data for new homes available in the literature, and through models. We also explored source control strategies and conclude that source removal is the most effective way to decrease chronic exposures to formaldehyde in existing homes. For new homes, reducing indoor sources and using pressed-wood with lower UF content are likely the best solutions. PRACTICAL IMPLICATIONS: Formaldehyde concentrations in homes due to indoor sources appear to persist throughout the lifetime of residences. Increases in ventilation rates are most effective in decreasing indoor concentrations in new homes where formaldehyde levels are high or when homes are tight. Consequently, other alternatives need to be promoted such as decreasing the amount of pressed-wood products with urea-formaldehyde (UF) resins in homes or reducing the UF content in these materials.

Particle loading rates for HVAC filters, heat exchangers, and ducts.

UNLABELLED: The rate at which airborne particulate matter deposits onto heating, ventilation, and air-conditioning (HVAC) components is important from both indoor air quality (IAQ) and energy perspectives. This modeling study predicts size-resolved particle mass loading rates for residential and commercial filters, heat exchangers (i.e. coils), and supply and return ducts. A parametric analysis evaluated the impact of different outdoor particle distributions, indoor emission sources, HVAC airflows, filtration efficiencies, coils, and duct system complexities. The median predicted residential and commercial loading rates were 2.97 and 130 g/m(2) month for the filter loading rates, 0.756 and 4.35 g/m(2) month for the coil loading rates, 0.0051 and 1.00 g/month for the supply duct loading rates, and 0.262 g/month for the commercial return duct loading rates. Loading rates are more dependent on outdoor particle distributions, indoor sources, HVAC operation strategy, and filtration than other considered parameters. The results presented herein, once validated, can be used to estimate filter changing and coil cleaning schedules, energy implications of filter and coil loading, and IAQ impacts associated with deposited particles. PRACTICAL IMPLICATIONS: The results in this paper suggest important factors that lead to particle deposition on HVAC components in residential and commercial buildings. This knowledge informs the development and comparison of control strategies to limit particle deposition. The predicted mass loading rates allow for the assessment of pressure drop and indoor air quality consequences that result from particle mass loading onto HVAC system components.

Biodistribution and radiation dose estimates for yttrium- and iodine-labeled monoclonal antibody IgG and fragments in nude mice bearing human colonic tumor xenografts.

An anti-carcinoembryonic antigen murine monoclonal antibody designated NP-4, and its F(ab')2 and Fab' fragments, were coupled to the 1/1 mixture of 1-isothiocyanato-benzyl-3-methyl- and 1-methyl-3-isothiocyanato-benzyl-diethylenetriaminepentaacetic acid chelate and labeled with 111In or 88Y. Biodistribution studies in nude mice bearing a human colonic tumor xenograft were performed with these labeled conjugates, and comparisons were made to unconjugated NP-4 IgG and fragments labeled with 131I. Regardless of the labeling method, higher tumor uptake was found with the intact IgG than with the fragments, but due to faster blood clearance, tumor/blood ratios were higher for the fragments than for the IgG. Tumor uptake for the radiometal-labeled NP-4 was generally higher than the 131I-labeled NP-4. Tumor/nontumor ratios for the liver, kidney, and spleen were higher for the 111In- and 88Y-labeled NP-4 IgG than the respective radiometal-labeled fragments, but tumor/nontumor ratios for the 131I-NP-4 fragments were higher than the 131I-NP-4 IgG. Radiometal uptake in the kidney was approximately 8 and 150 times higher than the 131I-NP-4 F(ab')2 and Fab', respectively, and the clearance of radiometal activity in the kidneys was approximately 10 times slower than the radioiodine. Quantitation of 88Y or 111In activity in the femur showed 3-5%/g for the IgG and F(ab')2 and only 1-2%/g for the Fab'. The amount of radioactivity in the femur remained constant over time, and between 60 and 100% of the 88Y activity remained after flushing the core of the femur with saline, whereas 50-70% of the 111In and only 25-30% of the 131I activity remained after washing. Radiation dose estimates derived from these studies suggest that at the maximal tolerated dose 131I-NP-4 IgG would deliver 5.9 times the dose to the tumor as 90Y-labeled NP-4 IgG. 90Y-labeled fragments would not be useful due to higher doses to the kidneys than to the tumor. However, with 131I-labeled IgG and fragments there is greater flexibility to permit tumoricidal doses without excessive toxicity to the normal tissues.

Estimates of red marrow dose by sacral scintigraphy in radioimmunotherapy patients having non-Hodgkin's lymphoma and diffuse bone marrow uptake.

According to the recommendations of the Dosimetry Task Group of the American Association of Physicists in Medicine, blood-derived estimates of the red marrow (RM) dose from radiolabeled monoclonal antibodies (MAbs) are valid only if the RM is devoid of any specific uptake. There is, therefore, a clear need for an alternative method for estimating the RM dose in patients receiving MAbs that target normal or abnormal (malignant) bone marrow elements. Radiolabeled LL2, an anti-B-cell murine MAb, targets normal B cells and malignant lymphoma cells in the RM. This may result in an increased radiation dose to the RM through neighboring targeted activity. We investigated whether imaging-based estimates of the RM dose, particularly using sacral scintigraphy, correlate with myelotoxicity in non-Hodgkin's lymphoma patients who received 131I-LL2. The sacrum-based RM dose (RMs) was estimated from sacral activity by assuming that 9.9% of the total adult RM is contained in the sacrum. The sacrum was not used if there was focally increased or decreased sacral uptake. Myelotoxicity was assessed based on Radiation Therapy Oncology Group criteria. Twelve of 21 non-Hodgkin's lymphoma patients treated had adequate imaging, dosimetry, and follow-up to evaluate myelotoxicity. Eight of these patients had diffusely increased RM uptake on their MAb scans. The average estimated RMs in the eight patients was 168 +/- 62 cGy (mean +/- SD) with only 50 mCi 131I-LL2. Six of these patients (75%) developed grade 3 or 4 myelotoxicity. In contrast, the average RMs in the four patients who did not have any enhanced uptake on their scans was 71 +/- 30 cGy (P < 0.02). None of these patients developed grade 3 or 4 toxicity. These results suggest that image-based estimates of the RM dose may be predictive of myelotoxicity and should be used in patients with diffuse RM uptake on their scans.

Tumor, red marrow, and organ dosimetry for 131I-labeled anti-carcinoembryonic antigen monoclonal antibody.

Tumor-, red marrow-, and organ-absorbed doses were calculated for patients receiving 131I-labeled monoclonal antibodies against carcinoembryonic antigen for either diagnosis or therapy. Ten patients with confirmed liver tumors who received doses ranging from 10.79 to 200 mCi were evaluated. Urine and blood samples were taken in order to determine total body and red marrow activity, respectively. Anterior and posterior gamma camera images were obtained at multiple times postinjection in order to quantitate activity uptake using the conjugate view counting method for the following organs and regions: lungs, liver, spleen, kidneys, and the liver tumors. In addition, sacral regions of interest were drawn to generate red marrow-absorbed dose estimates for comparison to those obtained by blood sampling. Tumor volumes were obtained from volumetric analysis of the patient's computed tomographic study and tumor S values were obtained by assuming uniform distribution of the 131I-labeled monoclonal antibody in spherical tumor regions considering all emitted electrons, beta-particles, and photons. The following mean absorbed doses in rads/mCi injected were obtained: lungs, 2.3 +/- 1.6 (SD); liver, 1.4 +/- 0.7; spleen, 2.6 +/- 1.4; kidneys, 3.1 +/- 1.5; total body, 0.7 +/- 0.5; red marrow from blood sampling, 2.9 +/- 1.9; red marrow from sacral scintigraphy, 1.7 +/- 1.2; and liver tumors, 69.3 +/- 92.5. Tumor volumes ranged from 1 to 216 g and the percentage of uptake/g of monoclonal antibody into these tumors ranged from 0.0006 to 1.040. There was a statistically significant difference between the two techniques for estimation of red marrow dose (P less than 0.01). This methodology, permits calculation of tumor, red marrow, and organ dosimetry using planar gamma camera imaging.

Radioimmunotherapy of the GW-39 human colonic tumor xenograft with 131I-labeled murine monoclonal antibody to carcinoembryonic antigen.

We have investigated the therapeutic efficacy of a single injection of 131I-labeled murine mouse monoclonal antibody (NP-4) against carcinoembryonic antigen using the human colonic tumor xenograft, GW-39, grown in the cheek pouches of adult hamsters. Therapeutic efficacy was dependent on the dose of radioactivity, the specificity of the antibody for the tumor, and the size of the tumor when the radioantibody was administered. A dose of 1 mCi of 131I-labeled NP-4 given 1 day after tumor transplantation completely inhibited the growth of 6 of 11 tumors over a 12-week period, and histological evidence indicated that viable tumor was absent in the tissue remaining at the injection site. Lower doses (0.5 mCi) of 131I-labeled NP-4 inhibited tumor growth over 90% in comparison to untreated animals, but the tumors eventually resumed growth. Delaying the administration of radioantibody for 4 or 7 days after tumor transplantation significantly reduced the therapeutic efficacy. Although the same dose of 131I-labeled irrelevant immunoglobulin G also inhibited tumor growth, 131I-labeled NP-4 was generally 2-3 times more effective in reducing tumor growth than was the control IgG. There was a 13% loss in body weight within 7 days after treatment with 1 mCi, but all the animals regained their weight by day 14, indicating that the level of radioactivity was tolerated well. Dosimetric calculations predicted that over 14 days a dose of nearly 2400 rads was delivered to the tumors with 131I-labeled NP-4. These results confirm our previous studies that 131I-labeled antibody can effectively inhibit tumor growth, but suggest that radioantibody therapy is most effectively administered when there is a low tumor burden.

Targeted therapy of athymic mice bearing GW-39 human colonic cancer micrometastases with 131I-labeled monoclonal antibodies.

The therapeutic potential of radiolabeled antibodies is usually evaluated in experimental animal models bearing s.c. xenografts. We have established a micrometastatic model of the GW-39 human colonic carcinoma in the nude mouse lung (J. Natl. Cancer Inst., 83: 627-632, 1991) and presented preliminary findings on the efficacy of a 131I-anticarcinoembryonic antigen (CEA) antibody in this model. We now extend our observations on the use of radioiodinated labeled monoclonal antibodies (MAbs) to treat multiple small tumor nodules. Biodistribution and dosimetry analysis was performed for intact and F(ab')2 of NP-4 anti-CEA IgG, Mu-9 anti-colon-specific antigen IgG, isotype-matched irrelevant anti-AFP IgG, and intact MAb 34A anti-lung endothelial IgG antibody. Comparisons were made for rad dose delivered to small s.c. tumors, normal lung, lung with tumor nodules, and isolated tumor nodules. Survival curves were generated for tumor-bearing animals treated 1, 7, or 14 days after tumor cell implantation with these antibodies using the maximal tolerated dose for intact antibodies (275 microCi) and for F(ab')2 fragments (1.2 mCi). The studies established the following observations: (a) in contrast to previous results in a bulky tumor model in hamsters, intact antibodies are more therapeutic than MAb fragments for both NP-4 and Mu-9; (b) tumor nodule size, even on the microscopic level, affects therapeutic outcome; antibodies were more effective when administered 7 days postimplantation (mean nodule diameter, 150 microns) compared with treatment 14 days postimplantation (mean nodule diameter, 750 microns); (c) administration of radioiodinated Mu-9 was exquisitely effective on single avascular tumor cells that had seeded in lung; irrelevant antibody was minimally radiotoxic; (d) as in the bulky disease model, the anti-colon-specific antigen p antibody delivers a higher rad dose than the anti-CEA antibody and is significantly more therapeutic in the micrometastasis model; (e) a higher affinity anti-CEA antibody (MN-14) recognizing the same epitope on CEA as NP-4 was equally therapeutic; (f) the use of MAb directed against the lung endothelium was not as therapeutic as a tumor-associated antibody; and (g) all tumor-associated antibodies were more efficacious than administration of the maximal tolerated dose of 5-fluorouracil and leucovorin in this human tumor-xenograft model. These results provide further support for the use of radioimmunotherapy in the handling of minimal disease, probably as part of an adjuvant treatment regimen.

Evaluation of a complementarity-determining region-grafted (humanized) anti-carcinoembryonic antigen monoclonal antibody in preclinical and clinical studies.

A complementarity-determining region-grafted (humanized) version of MN-14 (hMN-14), a high-affinity, anti-carcinoembryonic antigen (CEA) murine monoclonal antibody (mMAb), was selected from several clones that differed slightly in their framework composition. One clone was selected based on its similar binding affinity to CEA as that observed with mMN-14 MAb and its production yields. Targeting studies, using 131I-labeled humanized MN-14 (hMN-14)/125I-labeled mMN-14 IgG in GW-39 tumor-bearing nude mice, showed excellent tumor uptake and tumor: nontumor ratios, similar to the mMN-14. A pilot clinical imaging trial was initiated to determine the targeting, pharmacokinetics, and dosimetry for 131I-labeled hMN-14 IgG. Nineteen patients with advanced CEA-producing tumors were given 8 to 30 mCi (0.5 to 20.0 mg). Eleven patients also received 131I-labeled mMN-14 IgG for comparison. The biodistribution, tumor targeting, and pharmacokinetic behavior of the hMN-14 was similar to that seen with the mMN-14. The average time required to clear 50% of the radiolabeled hMN-14 from the blood and total body was 32.9 +/- 25.6 h and 109 +/- 73 h, respectively. Patients with elevated plasma CEA (i.e., > 200 ng/ml) had more than 30% of the labeled antibody complexed within 1 h after injection. In some of these patients, increased complexation resulted in enhanced metabolism of the antibody with more rapid clearance from the blood than that seen in patients with lower plasma CEA. The average radiation absorbed dose measured in 20 tumors (average weight, 204 +/- 205 g) in 14 patients was 7.6 +/- 5.3 cGy/mCi. Tumor: nontumor dose ratios were 2.5 +/- 1.6, 9.5 +/- 5.8, and 2.6 +/- 1.8 for the red marrow, total body, and liver, respectively. One patient, with a highly elevated human anti-mouse antibody response from a prior OncoScint study (murine B72.3 IgG), received 3 injections of the hMN-14 without an adverse experience, and showed no evidence of altered biodistribution characteristic of mMAb-human anti-mouse antibody interactions. An antibody response to hMN-14 (HAhMN14) was not detected in patients who received only the hMN-14 (as many as three injections), but in three patients who received two injections of the mMN-14, a HAhMN14 response was detected. With similar, excellent targeting properties as the mMN-14 and the potential for reduced immunogenicity, hMN-14 is an attractive candidate for further clinical imaging and therapy applications.